The Role of microRNAs in Inflammation

Abstract

Inflammation is a biological response of the immune system to various insults, such as pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-inflammatory factors and their direction towards inflammation often leads to the development and progression of various inflammation-associated diseases. The role of small non-coding RNAs (small ncRNAs) in inflammation has gained much attention in the past two decades for their regulation of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene regulation often turns out to be an important factor in controlling aberrant inflammatory reactions in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation.

Full text

Citation: Das, K.; Rao, L.V.M. The
Role of microRNAs in Inflammation.
Int. J. Mol. Sci. 2022,23, 15479.
https://doi.org/10.3390/
ijms232415479
Academic Editors: Mariana
Igoillo-Esteve, Flora Brozzi and
Romano Regazzi
Received: 11 November 2022
Accepted: 3 December 2022
Published: 7 December 2022
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International Journal of
Molecular Sciences
Review
The Role of microRNAs in Inflammation
Kaushik Das and L. Vijaya Mohan Rao *
Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler,
Tyler, TX 75708, USA
*Correspondence: vijay.rao@uthct.edu; Tel.: +1-903-877-7332; Fax: +1-903-877-7426
Abstract:
Inflammation is a biological response of the immune system to various insults, such as
pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-
inflammatory factors and their direction towards inflammation often leads to the development and
progression of various inflammation-associated diseases. The role of small non-coding RNAs (small
ncRNAs) in inflammation has gained much attention in the past two decades for their regulation
of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and
therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has
become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene
regulation often turns out to be an important factor in controlling aberrant inflammatory reactions
in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-
mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory
miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a
in inflammation.
Keywords: inflammation; microRNA; small non-coding RNA
1. Introduction
Inflammation is the immune system’s response against harmful stimuli, such as
pathogens [
1
], toxic compounds [
2
], damaged cells [
3
], or radiation [
4
], that aids in the
removal of injurious stimuli and starts the healing process in the damaged tissue [
5
]. In-
flammation thus acts as a defense mechanism of the system against harmful stimuli [
6
].
However, uncontrolled inflammation often leads to various chronic inflammatory syn-
dromes [
7
]. Therefore, a balance between the pro- and anti-inflammatory signals in the
host immune system is crucial to clearing the pathogen without causing extensive damage
to the host. Inflammation causes redness, tissue swelling, pain, heat generation, and a loss
of tissue functions. It often results in increased vascular permeability and the recruitment
of leukocytes to the infection site [
8
,
9
]. Recruited leucocytes are activated at the injury site
and release cytokines, which further extend the inflammatory response [10].
In the past few decades, one of the most important transformations in RNA biology
is the discovery of small (~20–30 nucleotides) non-coding RNAs (small ncRNAs), which
regulate gene expression at multiple levels. These regulations include the alteration in
chromatin structures [
11
], segregation of chromosomes [
12
], transcriptional regulation [
13
],
stability of RNA [
14
], and regulation of protein synthesis [
15
]. The regulatory effects of
small ncRNAs are generally considered inhibitory, as in most instances, they inhibit the
expression of their target genes. Based on their biological roles, origins, structures, and
targeted effector molecules, small ncRNAs are classified into three distinct populations:
microRNAs (miRNAs), short interfering RNAs (siRNAs), and Piwi-interacting RNAs
(piRNAs). The differences among the three forms of small ncRNAs are very subtle. mi- and
siRNAs are principally involved in the regulation of gene expression in eukaryotes [
16
];
however, in a few instances, they have also been found to play important roles in regulating
gene expression in prokaryotes [
17
,
18
]. In contrast, the piRNAs are found to be actively
Int. J. Mol. Sci. 2022,23, 15479. https://doi.org/10.3390/ijms232415479 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022,23, 15479 2 of 27
involved in gene regulation in both eukaryotes and prokaryotes [
19
,
20
]. The precursor
molecules for mi- and siRNAs are known to be double-stranded [
14
], whereas piRNAs’
precursors are believed to be single-stranded [
21
]. The effect of miRNAs is observed in both
the germlines and somatic lines of eukaryotes [
22
], whereas piRNAs exert their functions
more specifically in the germlines of eukaryotes [
23
]. Moreover, mi- and siRNAs bind to the
effector proteins, which belong to the AGO clade of Argonaute proteins, whereas piRNAs
bind to the Piwi clade proteins [14].
In the present review, we will focus on how the distinct classes of miRNAs influence
inflammatory responses in eukaryotes. We first discuss the biogenesis of miRNAs, the
mechanism of their action at the cellular level, and the regulation of their expression in
eukaryotic systems. Next, we briefly describe various pro- and anti-inflammatory miRNAs
and how they influence inflammation. Lastly, we provide a detailed discussion on miR-10a,
one of the prevalent anti-inflammatory miRNAs, on its chromosomal location, regulation
of its expression, its role in various inflammation-associated diseases, and its atypical
functions in the cells.
2. Biogenesis of miRNAs
The biogenesis of miRNAs starts with the co- or post-transcriptionally processing of
the transcripts synthesized by RNA polymerase II/III [
24
]. Half of the presently identified
miRNAs are derived from the processing of introns or a few protein-coding genes and
are classified as intragenic. In contrast, other miRNAs are intergenic, i.e., independently
transcribed and regulated through their own promoters [
25
,
26
]. Often, the transcription of
miRNAs occurs as a long transcript designated as ‘clusters’ with similar seeding regions
and thereby known as the miRNA family [
27
]. The biogenesis of miRNAs is comprised
two basic pathways: canonical and non-canonical.
In the canonical biogenesis pathway (Figure 1, left panel), the dominant pathway of
miRNA biogenesis, the pri-miRNAs, transcribed from their own genes, are processed to
generate the pre-miRNAs by a protein complex consisting of DiGeorge Syndrome Critical
Region 8 (DGCR8) and an RNase III enzyme family protein called Drosha [
28
]. pri-miRNA’s
N6-methyladenylated GGAC and other motifs are recognized by DGCR8 [
29
], followed
by subsequent cleavage of the pri-miRNA duplex at the base of the characteristic hairpin
structure by Drosha to generate 2–3 nucleotides 3’ overhang on pre-miRNAs [
30
]. The pre-
miRNAs thus generated are readily exported to the cytoplasm by the exportin-5/RanGTP
complex and subsequently processed by the RNase III endonuclease, Dicer [
28
,
31
]. Dicer
removes the terminal loop of pre-miRNAs to produce a mature miRNA duplex [
32
]. The 5’
end of the pre-miRNAs’ hairpin generates the 5p strand, whereas the 3p strand originates
from the 3’ end of the pre-miRNAs after Dicer cleavage. Then, an ATP-driven process
loads both strands of the mature miRNA duplex into the Argonaute (AGO) family proteins
(AGO1-4 in humans) [
33
]. The stability at the 5’ end of the miRNA duplex, or 5’ U
at nucleotide position 1, further determines the selection of 5p or 3p [
34
]. The AGO
preferentially picks up the strand with lower 5’ stability, or 5’ U. The other strand, the
passenger strand, is subsequently cleaved by AGO2 if no mismatch is found; otherwise,
the miRNA duplex with a central mismatch is passively degraded [24].
The non-canonical pathway of miRNA biogenesis (Figure 1, right panel) consists of
multiple pathways that involve different combinations of canonical pathway proteins,
Drosha, Dicer, exportin-5, and AGO2. These pathways can be classified into two major
groups, namely the DGCR8/Drosha-independent and the Dicer-independent pathways.
The pre-miRNAs of one of the DGCR8/Drosha-independent pathways include mirtrons,
which are generated from introns during mRNA splicing (Figure 1, right panel,
2

) [
35
,
36
].
Another form of the DGCR8/Drosha-independent pathway is the 7-methylguanosine
(m
7
G)-capped pre-miRNAs (Figure 1, right panel,
3

), which are released into the cytoplasm
via exportin-1 and do not require the Drosha cleavage [
37
]. On the other hand, in the
Dicer-independent pathway, miRNAs that include short hairpin RNA (shRNA) transcripts
are further processed by Drosha (Figure 1, right panel,
1

) and require AGO2 for their

Int. J. Mol. Sci. 2022,23, 15479 3 of 27
maturation in the cytoplasm [
38
]. pre-miRNA loading into AGO2 results in the slicing of
the 3p strand via 3’-5’ trimming [39], followed by the maturation of the 5p strand.
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 28
cytoplasm via exportin-1 and do not require the Drosha cleavage [37]. On the other hand,
in the Dicer-independent pathway, miRNAs that include short hairpin RNA (shRNA)
transcripts are further processed by Drosha (Figure 1, right panel, ①) and require AGO2
for their maturation in the cytoplasm [38]. pre-miRNA loading into AGO2 results in the
slicing of the 3p strand via 3’-5’ trimming [39], followed by the maturation of the 5p strand.
Figure 1. Biogenesis pathways of miRNAs. (Left panel) Canonical pathway. miRNA genes are
transcribed in the nucleus by RNA Pol-II or -III to generate pri-miRNAs, which are processed by
DGCR8-Drosha to produce pre-miRNAs. pre-miRNAs are transported via Exportin-5-Ran-GTP into
the cytoplasm, followed by further processing by Dicer to generate the miRNA duplex. miRNA
duplex then binds to AGO2, which further processes the duplex to produce one mature miRNA
strand while degrading the other strand. (Right panel) Non-canonical pathway. The non-canonical
pathway consists of multiple pathways: ① In Drosha-dependent but Dicer-independent pathway,
shRNAs are processed by DGCR8-Drosha, and are readily transported from the nucleus to the cy-
toplasm by Exportin-5-Ran-GTP. The transported miRNA duplex is processed by AGO2 (desig-
nated as AGO in the figure) to generate the mature miRNA. ② In one Drosha-independent and
Dicer-dependent pathway, Mirtrons, associated with spliceosomes, undergo debranching and trim-
ming to generate pre-miRNAs, which are transported into the cytoplasm by Exportin-5-Ran-GTP,
followed by sequential processing by Dicer and AGO1-4, respectively, to produce mature miRNAs.
③ In another Drosha-independent and Dicer-dependent pathway, (m
7
G)-capped pre-miRNAs are
released into the cytoplasm via exportin-1, followed by Dicer processing to form miRNA duplex,
which is further processed by AGO1-4 to generate mature miRNAs.
3. Mechanisms of miRNAs-Dependent Gene Regulation
miRNAs are usually known to bind to specific sequences at the 3’-UTR of their target
mRNA molecules, resulting in either translational repression or the degradation of the
target mRNA molecules [40,41].
miRNAs also bind to the 5’-UTR, the coding region, or
the promoter region of mRNAs [42]. The binding of miRNA to either the 5’-UTR or the
coding region of the target molecules results in the inhibition of gene expression [43,44].
In contrast, their binding at the promoter site enhances gene expression [45]. Here, we will
discuss the different modes of eukaryotic gene regulation by miRNAs.
4. miRNA-Dependent Gene Silencing Requires the miRISC
The miRNA-induced silencing complex (miRISC) includes the miRNA guide strand
and the AGO protein [46]. The complementary sequences in the target mRNAs (miRNA-
response elements; MREs) define the target specificity of the miRISC. Depending on this
Figure 1. Biogenesis pathways of miRNAs.
(
Left
panel) Canonical pathway. miRNA genes are
transcribed in the nucleus by RNA Pol-II or -III to generate pri-miRNAs, which are processed by
DGCR8-Drosha to produce pre-miRNAs. pre-miRNAs are transported via Exportin-5-Ran-GTP into
the cytoplasm, followed by further processing by Dicer to generate the miRNA duplex. miRNA
duplex then binds to AGO2, which further processes the duplex to produce one mature miRNA
strand while degrading the other strand. (
Right
panel) Non-canonical pathway. The non-canonical
pathway consists of multiple pathways:
1

In Drosha-dependent but Dicer-independent pathway,
shRNAs are processed by DGCR8-Drosha, and are readily transported from the nucleus to the
cytoplasm by Exportin-5-Ran-GTP. The transported miRNA duplex is processed by AGO2 (designated
as AGO in the figure) to generate the mature miRNA.
2

In one Drosha-independent and Dicer-
dependent pathway, Mirtrons, associated with spliceosomes, undergo debranching and trimming to
generate pre-miRNAs, which are transported into the cytoplasm by Exportin-5-Ran-GTP, followed by
sequential processing by Dicer and AGO1-4, respectively, to produce mature miRNAs.
3

In another
Drosha-independent and Dicer-dependent pathway, (m
7
G)-capped pre-miRNAs are released into
the cytoplasm via exportin-1, followed by Dicer processing to form miRNA duplex, which is further
processed by AGO1-4 to generate mature miRNAs.
3. Mechanisms of miRNAs-Dependent Gene Regulation
miRNAs are usually known to bind to specific sequences at the 3’-UTR of their target
mRNA molecules, resulting in either translational repression or the degradation of the
target mRNA molecules [
40
,
41
]. miRNAs also bind to the 5’-UTR, the coding region, or
the promoter region of mRNAs [
42
]. The binding of miRNA to either the 5’-UTR or the
coding region of the target molecules results in the inhibition of gene expression [
43
,
44
]. In
contrast, their binding at the promoter site enhances gene expression [
45
]. Here, we will
discuss the different modes of eukaryotic gene regulation by miRNAs.
4. miRNA-Dependent Gene Silencing Requires the miRISC
The miRNA-induced silencing complex (miRISC) includes the miRNA guide strand
and the AGO protein [
46
]. The complementary sequences in the target mRNAs (miRNA-
response elements; MREs) define the target specificity of the miRISC. Depending on this
complementarity, the target mRNA molecules are either sliced by AGO2 or degraded by
the miRISC, resulting in translational inhibition [
47
]. A 100% complementation between
the miRNA and mRNA would induce AGO2 endonuclease activity, which chops the target

Int. J. Mol. Sci. 2022,23, 15479 4 of 27
mRNA [
47
]. Interestingly, the extensive base-pairing also destabilizes the miRNA itself and
thus decrease amounts of miRNA [
48
,
49
]. In most cases, incomplete complementation [
50
]
results in the loss of AGO2’s endonuclease activity, thereby acting as a mediator of RNA
interference (as do other family members of AGO in humans: AGO1, -3, and -4). Sometimes,
a functional miRNA–mRNA interaction also occurs between nucleotides 2 to 7 at the 5’
seed region [
42
,
51
]. Moreover, additional base pairing at the 3’ end not only enhances
the stability but also increases the specificity of the miRNA–target interaction [
52
]. Once
the stable interaction is formed between miRNA and mRNA [
50
], the miRISC complex
further recruits the scaffolding protein, GW182 [
53
], which recruits the effector molecules
such as the poly(A)-deadenylase complexes PAN2-PAN3 and CCR4-NOT [
54
]. PAN2/3
initiates the poly(A)-deadenylation of the target mRNA molecule, which is completed by
CCR4-NOT. The deadenylation process is accelerated due to the interaction between the
tryptophan (W)-repeats of GW182 and poly(A)-binding protein C (PABPC) (Figure 2A,
1

) [
50
]. This is followed by a decapping reaction at the 5’ end, mediated by the decapping
protein 2 (DCP2) alongside other associators [
54
], and subsequent 5’-3’ degradation by
XRN1 (Figure 2A, 2
) [55].
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 4 of 28
complementarity, the target mRNA molecules are either sliced by AGO2 or degraded by
the miRISC, resulting in translational inhibition [47]. A 100% complementation between
the miRNA and mRNA would induce AGO2 endonuclease activity, which chops the tar-
get mRNA [47]. Interestingly, the extensive base-pairing also destabilizes the miRNA it-
self and thus decrease amounts of miRNA [48,49]. In most cases, incomplete complemen-
tation [50] results in the loss of AGO2’s endonuclease activity, thereby acting as a mediator
of RNA interference (as do other family members of AGO in humans: AGO1, -3, and -4).
Sometimes, a functional miRNA–mRNA interaction also occurs between nucleotides 2 to
7 at the 5’ seed region [42,51]. Moreover, additional base pairing at the 3’ end not only
enhances the stability but also increases the specificity of the miRNA–target interaction
[52]. Once the stable interaction is formed between miRNA and mRNA [50], the miRISC
complex further recruits the scaffolding protein, GW182 [53], which recruits the effector
molecules such as the poly(A)-deadenylase complexes PAN2-PAN3 and CCR4-NOT [54].
PAN2/3 initiates the poly(A)-deadenylation of the target mRNA molecule, which is com-
pleted by CCR4-NOT. The deadenylation process is accelerated due to the interaction be-
tween the tryptophan (W)-repeats of GW182 and poly(A)-binding protein C (PABPC)
(Figure 2A, ①) [50]. This is followed by a decapping reaction at the 5’ end, mediated by
the decapping protein 2 (DCP2) alongside other associators [54], and subsequent 5’-3’ deg-
radation by XRN1 (Figure 2A, ②) [55].
Figure 2. miRNAs-mediated gene regulation. (A) miRNA-mediated gene silencing mechanisms.
miRNA-dependent gene silencing occurs in three independent pathways. miRNA-bound AGO
Figure 2. miRNAs-mediated gene regulation.
(
A
) miRNA-mediated gene silencing mechanisms.
miRNA-dependent gene silencing occurs in three independent pathways. miRNA-bound AGO forms
the miRISC complex, which plays a central role in gene regulation.
1

miRISC recruits the scaffolding
protein, GW182, which further recruits effector complexes PAN2-3 and CCR4-NOT to induce the
deadenylation process. Deadenylation is enhanced by the interaction among GW182, PABPC, and

Int. J. Mol. Sci. 2022,23, 15479 5 of 27
CCR4-NOT through tryptophan (W) repeats.
2

GW182 recruits the decapping protein, DCP2, to
the 5’-m
7
G cap of the target mRNA molecules along with other associate proteins (such as EDP4,
DCP1, and DDX6), resulting in the decapping at the 5’ terminus. The decapped 5’-terminus becomes
vulnerable to cleavage by XRN1 due to its 5’-3’ exonuclease activity.
3

miRISC-GW182 also interferes
with the binding of ribosomes at the 5’ end of the mRNA molecules, resulting in translational
repression. (
B
) miRNA-mediated translational activation.
1

AGO2 and FXR1 bind to the AREs at
the 3’-UTR of the target mRNAs in the quiescent stage or during cell cycle arrest and induce the
translational process. 2
The same binding in proliferating stage suppresses the translation.
5. miRNA-Induced Translational Activation
Apart from their common role in suppressing gene expression, miRNAs, in some
instances, are also known to play an important part in the up-regulation of gene expression.
For example, AGO2 and another microRNA-protein complex (microRNP) family protein,
fragile-x-mental retardation-related protein 1 (FXR1), are shown to bind at the 3’-UTR
AU-rich elements (AREs) and activate the translational process (Figure 2B,
1

) [
56
]. Several
miRNAs play a dual role in different cell cycle stages. For example, let-7 during cell cycle
arrest is shown to activate the AGO2-FXR1-dependent translational process, whereas, in
proliferating stages, it inhibits protein synthesis (Figure 2B,
2

) [
56
]. The miRNA-mediated
translational activation is also observed in quiescent cells, such as oocytes, which essentially
require AGO2-FXR1 (Figure 2B,
1

) [
57
,
58
]. Under specific conditions, such as amino acid
deprivation, certain miRNAs are known to bind to the 5’-UTR of several mRNAs encoding
ribonuclear proteins (RNPs), thereby aiding in their translational activation [59].
6. miRNAs and Inflammation
Inflammation is primarily regulated by miRNAs through their altered expression in
certain immune cells [
60
]. As a part of the inflammatory response, the biogenesis of miRNAs
is often regulated at different stages, such as the synthesis, processing, and stabilization of
pre- or mature miRNAs [
61
,
62
]. miRNAs regulate different stages of inflammation, starting
from initiation, expansion, and resolution by both positive and negative feedback [
63
]. In
the positive feedback, the array of events restricts not only the invasion of pathogens but
also the successful repair of tissue damage. In contrast, the negative feedback, activated
during severe inflammation, helps maintain tissue homeostasis. In the following section,
we briefly discuss how various pro- and anti-inflammatory miRNAs (Figure 3) exert their
effects (Tables 1and 2). We limit our discussion to a few selective and prevalent miRNAs,
with specific emphasis on miR-10a, one of the most abundant and prevalent endothelial
anti-inflammatory miRNAs associated with several disease conditions.
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 5 of 28
forms the miRISC complex, which plays a central role in gene regulation. ① miRISC recruits the
scaffolding protein, GW182, which further recruits effector complexes PAN2-3 and CCR4-NOT to
induce the deadenylation process. Deadenylation is enhanced by the interaction among GW182,
PABPC, and CCR4-NOT through tryptophan (W) repeats. ② GW182 recruits the decapping pro-
tein, DCP2, to the 5’-m
7
G cap of the target mRNA molecules along with other associate proteins
(such as EDP4, DCP1, and DDX6), resulting in the decapping at the 5’ terminus. The decapped 5’-
terminus becomes vulnerable to cleavage by XRN1 due to its 5’-3’ exonuclease activity. ③ miRISC-
GW182 also interferes with the binding of ribosomes at the 5’ end of the mRNA molecules, resulting
in translational repression. (B) miRNA-mediated translational activation. ① AGO2 and FXR1 bind
to the AREs at the 3’-UTR of the target mRNAs in the quiescent stage or during cell cycle arrest and
induce the translational process. ② The same binding in proliferating stage suppresses the transla-
tion.
5. miRNA-Induced Translational Activation
Apart from their common role in suppressing gene expression, miRNAs, in some
instances, are also known to play an important part in the up-regulation of gene expres-
sion. For example, AGO2 and another microRNA-protein complex (microRNP) family
protein, fragile-x-mental retardation-related protein 1 (FXR1), are shown to bind at the 3’-
UTR AU-rich elements (AREs) and activate the translational process (Figure 2B, ①) [56].
Several miRNAs play a dual role in different cell cycle stages. For example, let-7 during
cell cycle arrest is shown to activate the AGO2-FXR1-dependent translational process,
whereas, in proliferating stages, it inhibits protein synthesis (Figure 2B, ②) [56]. The
miRNA-mediated translational activation is also observed in quiescent cells, such as oo-
cytes, which essentially require AGO2-FXR1 (Figure 2B, ①) [57,58]. Under specific condi-
tions, such as amino acid deprivation, certain miRNAs are known to bind to the 5’-UTR
of several mRNAs encoding ribonuclear proteins (RNPs), thereby aiding in their transla-
tional activation [59].
6. miRNAs and Inflammation
Inflammation is primarily regulated by miRNAs through their altered expression in
certain immune cells [60]. As a part of the inflammatory response, the biogenesis of miR-
NAs is often regulated at different stages, such as the synthesis, processing, and stabiliza-
tion of pre- or mature miRNAs [61,62]. miRNAs regulate different stages of inflammation,
starting from initiation, expansion, and resolution by both positive and negative feedback
[63]. In the positive feedback, the array of events restricts not only the invasion of patho-
gens but also the successful repair of tissue damage. In contrast, the negative feedback,
activated during severe inflammation, helps maintain tissue homeostasis. In the following
section, we briefly discuss how various pro- and anti-inflammatory miRNAs (Figure 3)
exert their effects (Tables 1 and 2). We limit our discussion to a few selective and prevalent
miRNAs, with specific emphasis on miR-10a, one of the most abundant and prevalent
endothelial anti-inflammatory miRNAs associated with several disease conditions.
Figure 3. A list of pro- and anti-inflammatory miRNAs in the context of various disease conditions.
Figure 3. A list of pro- and anti-inflammatory miRNAs in the context of various disease conditions.

Int. J. Mol. Sci. 2022,23, 15479 6 of 27
Table 1. Pro-inflammatory miRNAs and their targets and functions.
miRNAs Cell Type Target(s) Functions Reference(s)
miR-155 Macrophages FADD, IKKε, Ripk1 LPS-induced miR-155 promotes
inflammation by inducing TNF-αsecretion [64]
miR-92a ECs KLF4
Atheroprone stimuli release miR-92a-laden
EVs that confer pro-inflammation to
macrophages
[65]
miR-200 VSMCs Zeb-1
miR-200 expression is increased in VSMCs
from diabetic mice and induces
inflammation
[66]
miR-23a M1-macrophages A20, JAK1, STAT6
Down-regulation of miR-23a in
M1-macrophages activates NF-kB
pro-inflammatory pathway while inhibiting
anti-inflammatory pathway
[67]
miR-27a M1-macrophages IRF-4, PPAR-γSame phenotypic response as miR-23a [67]
miR-29c Podocytes TTP miR-29c up-regulation in podocytes of
diabetic mice induces inflammation [68]
miR-138 Macrophages SIRT1
LPS stimulation induces miR-138 which
activates NF-kB pro-inflammatory signaling
pathway
[69]
miR-34a/c Epidermal
keratinocytes LGR4
miR-34a is up-regulated in wound-edge
epidermal keratinocytes of venous ulcers
and induces the release of pro-inflammatory
cytokines
[70]
miR-132
Primary pre-adipocytes
SIRT1
Serum deprivation induces miR-132
expression in human primary
preadipocytes, which induces the release of
pro-inflammatory cytokines
[71]
let-7a ECs IkBβ
In atherosclerotic ECs, the increased level of
let-7a activates NF-kB pro-inflammatory
pathway
[72]
Abbreviations: ECs, endothelial cells; VSMCs, vascular smooth muscle cells.
Table 2. Anti-inflammatory miRNAs, their targets, and functions.
miRNAs Cell Type Target(s) Functions Reference(s)
miR-126 ECs SPRED1, PI3KR2,
VCAM-1
miR-126 exerts anti-inflammatory effects
and is found to be down-regulated upon
SCI
[73]
miR-146a Macrophages TRAF6, IRAK1
miR-146a exhibits anti-inflammatory
responses and is down-regulated after the
induction of diabetes
[74]
miR-124 Macrophages STAT3, TACE
After LPS exposure, cholinergic agonists
induce miR-124 expression that controls the
inflammation
[75]
miR-125b Chondrocytes TRAF6
miR-125b expression is down-regulated in
osteoarthritic conditions and the activation
of NF-kB pro-inflammatory pathway results
[76]
miR-31 Colonic epithelial cells GP130, IL17R, IL17RA
After CD or UC, miR-31 expression is
increased to control prolonged colonic
inflammation
[77]

Int. J. Mol. Sci. 2022,23, 15479 7 of 27
Table 2. Cont.
miRNAs Cell Type Target(s) Functions Reference(s)
miR-210 Chondrocytes DR6
miR-210 expression goes down in
osteoarthritic conditions causing
inflammation
[78]
miR-24 Macrophages, aortic
SMCs, ECs Chi3l1
miR-24 down-regulation in AAA causing
cytokines production from macrophages
and SMCs, expression of cell-adhesion
molecules in ECs
[79]
miR-149 Chondrocytes TAK1
In osteoarthritis, miR-149 expression is
decreased thereby activating NF-kB
pro-inflammatory pathway
[80]
miR-181a Kidney cells TNF-α
In DN, miR-181a expression is
down-regulated, causing the activation of
TNF-α-mediated inflammatory response
[81]
miR-150 Macrophages STAT1 Down-regulation of miR-150 by LPS
activates pro-inflammatory responses [82]
miR-143 Pulmonary epithelial
cells MyD88
Down-regulated miR-143 expression in
fibromyalgia causes pro-inflammatory
responses
[83]
miR-9 Macrophages JAK1, MMP-13
oxLDL, LPS, or Alum-stimulated
macrophages down-regulate miR-9
expression and activate the inflammasome
[84]
miR-142 Macrophages IRAK-1
BCG infection down-regulates miR-142
expression in macrophages to activate
NF-kB pro-inflammatory pathway
[85]
miR-223 HGFs IKKα, MKP-5
Inflammatory cytokines induce miR-223
expression in HGFs which in turn induce
pro-inflammatory cytokines
[86]
miR-21 Macrophages KBTBD7
Excessive inflammation by DAMPs after MI
induces miR-21 expression, which produces
anti-inflammatory responses to control
prolonged inflammation in post-MI
[87]
Abbreviations: ECs, endothelial cells; SCI, spinal cord injury; CD, Crohn’s disease; UC, ulcerative colitis; SMCs,
smooth muscle cells; AAA, abdominal aortic aneurysm; DN, diabetic nephropathy; oxLDL, oxidized low-density
lipoprotein; BCG, Bacillus Calmette–Guèrin; HGFs, human gingival fibroblasts; DAMPs, damage-associated
molecular patterns; MI, myocardial infarction.
7. Pro-Inflammatory miRNAs
miR-155 is considered one of the most abundant pro-inflammatory miRNAs [
88
], ex-
pressed in a wide variety of cells, such as monocytes, macrophages, activated B cells, T cells,
etc., and allows the translation of pro-inflammatory cytokine, TNF-
α
[
64
]. The expression of
miR-155 is often induced by LPS [
64
], and the anti-inflammatory cytokine IL-10 is known to
down-regulate miR-155 expression [
89
]. LPS governs the expression of miR-155 via the ac-
tivation of the MyD88 and TRIF pathways [
88
]. miR-155 knock-out mice are shown to have
an impaired immune response against Salmonella infection due to defects in B- and T-cell
activation and are difficult to immunize against this pathogen [
90
]. Another study indicated
that miR-155 knock-out mice show a significant reduction in the number of B-cell germinal
centers, whereas miR-155 over-expressive mice show elevated numbers of them [
91
]. All
these studies indicate the importance of miR-155 in the pro-inflammatory response.
The expression of another pro-inflammatory miRNA, miR-92a, is significantly up-
regulated in atherogenic endothelial cells (EC), and the transfer of miR-92a via extra-
cellular vesicles (EVs) from EC to macrophages results in the up-regulation of several
pro-inflammatory genes in the recipient macrophages [
65
]. miR-200 family miRNAs show

Int. J. Mol. Sci. 2022,23, 15479 8 of 27
pro-inflammatory response via targeting Zeb-1 and up-regulating cyclooxygenase-2 and
MCP-1 in vascular smooth muscle cells in the type 2 diabetic murine model [66]. Another
miRNA, miR-23a, not only activates pro-inflammatory NF-kB signaling via targeting A20,
but also suppresses the anti-inflammatory JAK1/STAT6 pathway upon targeting both JAK1
and STAT6 directly in macrophages [
67
]. miR-27a shows the same phenotypic response
upon targeting IRF4 and PPAR-γ[67].
miR-29c is shown to be involved in exerting a pro-inflammatory response in patients
with diabetic nephropathy by targeting tristetraprolin (TTP) [
68
]. miR-138 participates
in the macrophage inflammatory response via targeting SIRT1 and activating the NF-kB
signaling pathway [
69
]. miR-34 family miRNAs, such as miR-34a and -34c, are also shown
to induce the release of pro-inflammatory cytokines and chemokines in the wound-edge
epidermal keratinocytes of venous ulcers via targeting LGR4, thereby delaying the wound
closure and contributing the pathological roles in venous ulcers [70].
Another miRNA, miR-132, is found to be up-regulated in LPS-challenged THP-1
macrophages [
92
] and associated with the pro-inflammatory response via the release of
IL-8 and MCP-1 by regulating SIRT1 in starved adipose-derived stem cells [
71
]. miR-132
could be a biomarker for inflammatory bowel disease (IBD) [
93
] and rheumatoid arthritis
(RA) [
94
]. Let-7a confers a pro-inflammatory response via targeting IkB
β
, leading to
NF-kB activation and subsequent expression of inflammatory and adhesion molecules in
endothelial cells [72].
8. Anti-Inflammatory miRNAs
miR-7 and miR-10a are the most abundant anti-inflammatory miRNAs and are known
to be associated with various disease conditions. We will discuss them in detail, particularly
miR-10a, after a brief discussion of other anti-inflammatory miRNAs.
Other than miR-10a and miR-7, several anti-inflammatory miRNAs are associated
with various disease conditions. miR-126, another abundant endothelial miRNA, inhibits
vascular inflammation by targeting the Sprouty-related EVH1 domain-containing protein
1 (SPRED1), phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2), and vascular cell
adhesion molecule 1 (VCAM1) in spinal cord injury (SCI), and miR-126 therapy could be
used as a potential therapeutic approach in recovery after contusion in SCI [73].
Another anti-inflammatory miRNA, miR-146a, plays a pivotal role in the pathogen-
esis of diabetic nephropathy, and miR-146a deficiency leads to the increased expression
of inflammatory cytokines IL-1
β
, IL-18, and other markers of inflammasome activation
in macrophages [
74
]. miR-124 is also known to mediate cholinergic anti-inflammatory
response by targeting STAT3 and TACE, thereby limiting IL-6 and TNF-
α
secretion from
macrophages [
75
]. miR-125b confers its anti-inflammatory potential by targeting TRAF6-
mediated MAPK and NF-kB signaling, thus regulating IL-1β-induced inflammatory gene
expression in human osteoarthritic chondrocytes [76].
miR-31 reduces the inflammatory response and promotes the regeneration of colon
epithelium in mice [
77
]. miR-210, on the other hand, prohibits the NF-kB inflammatory sig-
naling upon targeting DR6 in osteoarthritis [
78
]. miR-24 limits aortic vascular inflammation
by inhibiting chitinase 3-like 1 (Chi3l1)-induced synthesis of pro-inflammatory cytokines in
macrophages and restricts abdominal aneurysm development in mice [79].
miR-149 shows its anti-inflammatory response via targeting TAK1/NF-kB signaling
in osteoarthritic chondrocytes [
80
]. miR-181a down-regulates TNF-
α
, thereby improving
renal inflammation in the diabetic nephropathy animal model [
81
]. The down-regulation
of miR-150 induces the LPS-mediated release of pro-inflammatory cytokines in THP-1
macrophages via STAT1 up-regulation [
82
]. miR-143, on the other hand, down-regulates
the TLR4/MyD88/NF-kB pathway and confers its anti-inflammatory potential in pul-
monary epithelial cells [
83
]. miR-9 is known to inhibit the formation of inflammasomes
and down-regulate inflammation in atherosclerosis by targeting the JAK1/STAT1 path-
way in macrophages [
84
]. miR-142 also shows its anti-inflammatory response in murine
macrophages through targeting IRAK1 and inhibiting the synthesis of pro-inflammatory

Int. J. Mol. Sci. 2022,23, 15479 9 of 27
NF-
κ
B1, TNF-
α
, and IL-6 [
85
]. miR-223 modulates the inflammatory response by inhibiting
IKK
α
and MKP5 in human gingival fibroblasts [
86
]. It also suppresses TLR4 signaling
in macrophages [
95
] and intestinal inflammasome formation [
96
]. miR-21 plays a pivotal
role in controlling excessive inflammation by DAMPs after MI via targeting KBTBD7 in
macrophages, thereby making miR-21 a potential therapeutic target in the treatment of
MI [87].
9. miR-7
miR-7 is animportant anti-inflammatory miRNA [
97
] thatplays significant roles in
various diseases, such as cancer, cardiovascular diseases, and pregnancy-associated diseases
(Table 3).
Cancer:
miR-7 plays a pivotal role in the growth and development of various tumors.
The expression of miR-7 is shown to be down-regulated in metastatic breast cancer tissues
as compared to normal breast tissues, and the down-regulation of miR-7 often leads to
the induction of breast cancer cell growth, invasiveness, migration, proliferation, and
stemness, while preventing apoptosis [
98
]. Reddy et al. showed that miR-7 introduction
into invasive breast cancer cells leads to the inhibition of cancer cell migration, invasiveness,
and anchorage-independent growth via down-regulating its target, P21-activated kinase
1 (PAK1) expression [
99
]. Kong et al. [
100
] demonstrated that in breast cancer cells, miR-
7 inhibits the expression of focal adhesion kinase (FAK) by directly targeting it. This
leads to the suppression of epithelial–mesenchymal transition (EMT) and breast cancer
metastasis [
100
]. miR-7 also targets Krüppel-like factor 4 (KLF4) in breast cancer stem-like
cells (CSC) and impedes their metastasis to the brain [
101
]. Li et al. demonstrated that
miR-7-dependent targeting of HoxB3 prevents tumor growth and suppresses the colony-
formation ability of breast cancer cells [
102
]. Other studies showed that miR-7 perturbs the
invasive potential of human breast cancer cells and sensitizes them to DNA damage via
directly targeting SET domain-containing (lysine methyltransferase) 8 (SET8) [103].
In lung cancer, miR-7 down-regulation often leads to the progression of the tumor
growth. For example, miR-7 suppresses the proliferation of lung cancer cells by targeting
the epidermal growth factor receptor (EGFR) [
104
]. miR-7 is also shown to target the
anti-apoptotic protein BCL-2 in lung cancer cells, which leads to the suppression of cell
proliferation and the promotion of tumor cell apoptosis [
105
]. miR-7 is shown to down-
regulate the expression of proteasome activator 28 (PA28) subunit
γ
in non-small cell lung
cancer, leading to the induction of apoptosis and cell cycle arrest [
106
]. miR-7 is also shown
to target phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) in lung cancer cells, and
the down-regulation of the PIK3R3/Akt pathway attenuates the TLR9 signaling-induced
growth and proliferation of lung cancer cells [107].
A growing body of evidence indicates that miR-7 plays an important role in brain
tumor development [
108
]. miR-7 is shown to inhibit glioblastoma progression by directly
targeting EGFR and its downstream signaling molecules, PI3K and Raf-1 [
109
]. Similar to
breast cancer, miR-7 also targets FAK1 in brain cancer cells, thereby inhibiting tumor cell
proliferation and angiogenesis [110].
In colorectal cancer, miR-7 down-regulates the expression of paired box 6 (PAX6),
which limits the PI3K/ERK-dependent up-regulation of MMP2 and MMP9 and hence
inhibits colorectal cancer cell growth, proliferation, and metastasis [
111
]. miR-7 also in-
hibits the growth and metastasis of hepatocellular carcinoma by targeting AKT and down-
regulating the PI3K/AKT pathway [
112
]. Zhao et al. showed that miR-7 inhibits gastric
cancer metastasis by targeting insulin-like growth factor 1 (IGF-1) and IGF-1-mediated
induction of EMT [113].
Cardiovascular diseases:
Kaneto et al. demonstrated that miR-7 expression is up-
regulated in the serum of patients suffering from left ventricular hypertrophy (LVH),
and miR-7 serves as a biomarker for cardiovascular anomalies [
114
]. miR-7 is shown
to suppress the growth and development of platelet-derived growth factor (PDGF)-BB-
stimulated vascular smooth muscle cells (VSMCs) via targeting EGFR and could be used as

Int. J. Mol. Sci. 2022,23, 15479 10 of 27
a therapeutic regimen against cardiovascular diseases [
115
]. miR-7 is thought to serve as a
biomarker for coronary atherosclerotic heart disease (CHD) [
116
] and cardiac sarcoidosis
(CS) [117].
Pregnancy-associated disease:
miR-7 was identified in the islet cells of the embryonic
pancreas and could serve as a biomarker for diabetic embryopathy (DE) [
118
]. Complica-
tions during pregnancy often result from abnormal trophoblast invasion, and EMT plays a
pivotal role in this process. miR-7 is shown to target EMT-related transcription factors and
downregulate the mesenchymal markers, ultimately inhibiting trophoblast mesenchymal
transition [119,120].
Table 3. The role of miR-7 in various diseases.
Disease Cell Type Expression Target(s) Function Reference(s)
Cancer BC cells Down PAK1 Inhibits cell migration, invasiveness,
anchorage-dependent growth [99]
BC cells Down FAK Inhibits BC metastasis [100]
BC stem-like
cells Down KLF-4 Inhibits metastasis to the brain [101]
BC cells Down HoxB3 Inhibits tumor growth and
colony-forming ability of BC cells [102]
BC cells Down SET8 Decreases invasive potential and
sensitizes the cells to DNA damage [103]
LC cells Down EGFR Suppresses proliferation [104]
LC cells Down BCL-2 Perturbs proliferation and promotes
apoptosis [105]
Non-small LC
cells Down PA28 subunit γInduction of apoptosis and cell-cycle
arrest [106]
LC cells Down PIK3R3 Retards growth and proliferation [107]
Glioblastoma Down EGFR, PI3K, Raf-1 Prevents growth and development [109]
Brain cancer cells
Down FAK1 Inhibits tumor proliferation and
angiogenesis [110]
Colorectal cancer
cells Down PAX6 Prevents growth, proliferation, and
metastasis [111]
HC cells Down AKT Inhibits growth and metastasis [112]
GC cells Down IGF-1 Inhibits GC growth [113]
CVD VSMCs Up EGFR Suppresses VSMCs growth and
development [114]
DE Islet cells Up EMT-TFs Inhibits trophoblast mesenchymal
transition [119]
Abbreviations: BC, breast cancer; LC, lung cancer; HC, hepatocellular carcinoma; GC, gastric cancer; CVD,
cardiovascular disease; VSMCs, vascular smooth muscle cells, DE, diabetic embryopathy.
10. miR-10a
miR-10a is considered to be a key post-transcriptional mediator in controlling inflam-
matory responses [
121
]. The actions of miR-10a are well-conserved among vertebrates, and
its role is well-established in several inflammatory disorders such as rheumatoid arthritis
(RA), inflammatory bowel disease (IBD), colitis, acute pancreatitis (AP), atherosclerosis,
sepsis, cancer, etc. [122–129].
11. miR-10a Chromosomal Location
Genes encoding miR-10 family members are located within the homeobox (Hox) gene
clusters [
130
], the transcription factors that critically regulate anterior–posterior patterning

Int. J. Mol. Sci. 2022,23, 15479 11 of 27
in bilaterian animals [
131
]. miR-10 is known to be co-expressed with Hox genes during
development [
132
] and targets Hox transcripts [
133
], thereby believed to play a crucial role
in determining body plans. Mammalian miR-10 family members miR-10a and miR-10b
lie upstream of HoxB4 and HoxD4, respectively [
134
]. Due to the high degree of sequence
conservation, differing only by a single nucleotide at the eleventh position (U and A for
miR-10a and miR-10b, respectively), they target overlapping sequences in mRNAs [
135
].
Although miR-10a/b is shown to target Hox transcripts, a growing body of evidence
indicates that various other pathways are also regulated by miR-10a/b [
130
]. Most of the
mature miR-10 family members are generated from the 5’-arm of the hairpin precursors,
whereas, in some instances, arm-switching results in the formation of mature miR-10 from
the opposite arm [136].
12. Regulation of miR-10a Expression
Being a part of the Hox gene clusters, miR-10a/b are assumed to be regulated by
cis-regulatory elements of the neighboring Hox genes. For example, prenatal exposure of
fetal mouse brain to ethanol often leads to the co-expression of miR-10a/b and their associ-
ated Hox genes [
137
]. Moreover, miR-10a expression is often regulated by transcription
factors p65 and TWIST1 (Figure 4) [
138
,
139
]. The inhibition of p65 nuclear translocation
significantly reduces retinoic acid-induced miR-10a expression in embryonic stem cells,
which prohibits their differentiation into smooth muscle cells [
139
]. On the other hand,
TWIST1 is shown to enhance the expression of miR-10a in CD34
+
cells in myelodysplastic
syndrome, and TWIST1/miR-10a-axis could be used as a therapeutic target in the treatment
of the myelodysplastic syndrome [
138
]. The regulation of miR-10a is also mediated by
DNA methylation at the promoter region by knocking down both DNA methyltransferases,
DNMT1 and DNMT3b, significantly increasing the expression of miR-10a in human colon
cancer cells [140].
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 12 of 28
11. miR-10a Chromosomal Location
Genes encoding miR-10 family members are located within the homeobox (Hox)
gene clusters [130], the transcription factors that critically regulate anterior–posterior
patterning in bilaterian animals [131]. miR-10 is known to be co-expressed with Hox genes
during development [132] and targets Hox transcripts [133], thereby believed to play a
crucial role in determining body plans. Mammalian miR-10 family members miR-10a and
miR-10b lie upstream of HoxB4 and HoxD4, respectively [134]. Due to the high degree of
sequence conservation, differing only by a single nucleotide at the eleventh position (U
and A for miR-10a and miR-10b, respectively), they target overlapping sequences in
mRNAs [135]. Although miR-10a/b is shown to target Hox transcripts, a growing body of
evidence indicates that various other pathways are also regulated by miR-10a/b [130].
Most of the mature miR-10 family members are generated from the 5’-arm of the hairpin
precursors, whereas, in some instances, arm-switching results in the formation of mature
miR-10 from the opposite arm [136].
12. Regulation of miR-10a Expression
Being a part of the Hox gene clusters, miR-10a/b are assumed to be regulated by cis-
regulatory elements of the neighboring Hox genes. For example, prenatal exposure of fetal
mouse brain to ethanol often leads to the co-expression of miR-10a/b and their associated
Hox genes [137]. Moreover, miR-10a expression is often regulated by transcription factors
p65 and TWIST1 (Figure 4) [138,139]. The inhibition of p65 nuclear translocation signifi-
cantly reduces retinoic acid-induced miR-10a expression in embryonic stem cells, which
prohibits their differentiation into smooth muscle cells [139]. On the other hand, TWIST1
is shown to enhance the expression of miR-10a in CD34
+
cells in myelodysplastic syn-
drome, and TWIST1/miR-10a-axis could be used as a therapeutic target in the treatment
of the myelodysplastic syndrome [138]. The regulation of miR-10a is also mediated by
DNA methylation at the promoter region by knocking down both DNA methyltransfer-
ases, DNMT1 and DNMT3b, significantly increasing the expression of miR-10a in human
colon cancer cells [140].
Figure 4. Regulation of miR-10a expression. (A) miR-10a induction. Transcription factors p65 and
TWIST1 bind to the promoter region of the miR-10a gene resulting in the induction of miR-10a ex-
pression. (B) miR-10a suppression. DNA methyltransferases DNMT1 and DNMT3b cause promoter
methylation of the miR-10a gene resulting in the down-regulation of miR-10a expression.
13. Targets of miR-10a in the Context of Various Inflammation-Associated Diseases
Rheumatoid arthritis (RA): miR-10a, a central regulator in the NF-ĸB signaling path-
way, is often shown to regulate multiple inflammation-associated diseases (Figure 5 and
Table 4). In RA patients, fibroblast-like synoviocytes (FLSs) are known to play an im-
portant role in cartilage and joint damage, deformation, and destruction [141]. Persistent
Figure 4. Regulation of miR-10a expression.
(
A
) miR-10a induction. Transcription factors p65
and TWIST1 bind to the promoter region of the miR-10a gene resulting in the induction of miR-
10a expression. (
B
) miR-10a suppression. DNA methyltransferases DNMT1 and DNMT3b cause
promoter methylation of the miR-10a gene resulting in the down-regulation of miR-10a expression.
13. Targets of miR-10a in the Context of Various Inflammation-Associated Diseases
Rheumatoid arthritis (RA):
miR-10a, a central regulator in the NF-kB signaling path-
way, is often shown to regulate multiple inflammation-associated diseases (Figure 5and
Table 4). In RA patients, fibroblast-like synoviocytes (FLSs) are known to play an important
role in cartilage and joint damage, deformation, and destruction [
141
]. Persistent activation
of the NF-kB signaling pathway and the concomitant release of pro-inflammatory cytokines
by the FLSs often contribute to the etiopathogenesis of RA [
142
]. Mu et al. observed a
significant down-regulation of miR-10a expression in FLSs of RA patients as compared
to osteoarthritis controls, leading to the activation of the NF-
κ
B signaling pathway by
up-regulating miR-10a target genes—interleukin-1 receptor-associated kinase 4 (IRAK4),

Int. J. Mol. Sci. 2022,23, 15479 12 of 27
transforming growth factor beta (TGF-
β
)-activated kinase 1 (TAK1). beta-transducin re-
peat containing E3 ubiquitin ligase (
β
-TrCP), and mitogen-activated protein 3 kinase 7
(MAP3K7) [
126
]. This leads induction of several pro-inflammatory cytokines, such as
TNF-
α
, IL-1
β
, etc., which in turn down-regulate miR-10a expression via NF-
κ
B-dependent
activation of the transcription factor YY1 [
126
]. Thus, miR-10a plays a crucial role in control-
ling this regulatory circuit and could be an important therapeutic target for the treatment
of RA. Hussain et al. have shown that in inflamed synoviocytes, the down-regulation of
miR-10a promotes cell proliferation while restricting apoptosis, thereby contributing to the
pathogenesis of RA [
143
]. Stimulation of the human synovial sarcoma cell line SW982 with
IL-1
β
inhibits the expression of miR-10a, leading to the up-regulation of its target gene,
T-box transcription factor 5 (TBX5), which induces the proliferation of synoviocytes and
suppression of synoviocyte apoptosis in RA [
143
]. Thus, miR-10a is considered a biomarker
of RA diagnosis and therapy [144].
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 13 of 28
activation of the NF-ĸB signaling pathway and the concomitant release of pro-inflamma-
tory cytokines by the FLSs often contribute to the etiopathogenesis of RA [142]. Mu et al.
observed a significant down-regulation of miR-10a expression in FLSs of RA patients as
compared to osteoarthritis controls, leading to the activation of the NF-κB signaling path-
way by up-regulating miR-10a target genes—interleukin-1 receptor-associated kinase 4
(IRAK4), transforming growth factor beta (TGF-β)-activated kinase 1 (TAK1). beta-trans-
ducin repeat containing E3 ubiquitin ligase (β-TrCP), and mitogen-activated protein 3 ki-
nase 7 (MAP3K7) [126]. This leads induction of several pro-inflammatory cytokines,
such as TNF-α, IL-1β, etc., which in turn down-regulate miR-10a expression via NF-κB-
dependent activation of the transcription factor YY1 [126]. Thus, miR-10a plays a crucial
role in controlling this regulatory circuit and could be an important therapeutic target for
the treatment of RA. Hussain et al. have shown that in inflamed synoviocytes, the down-
regulation of miR-10a promotes cell proliferation while restricting apoptosis, thereby con-
tributing to the pathogenesis of RA [143]. Stimulation of the human synovial sarcoma cell
line SW982 with IL-1β inhibits the expression of miR-10a, leading to the up-regulation of
its target gene, T-box transcription factor 5 (TBX5), which induces the proliferation of syn-
oviocytes and suppression of synoviocyte apoptosis in RA [143]. Thus, miR-10a is consid-
ered a biomarker of RA diagnosis and therapy [144].
Figure 5. Various inflammation-associated diseases regulated by miR-10a. miR-10a is a key regu-
latory molecule that influences several inflammation-associated diseases, such as rheumatoid ar-
thritis (RA), inflammatory bowel disease (IBD), colitis, acute pancreatitis (AP), sepsis, atherosclero-
sis, and cancer.
Osteoarthritis (OA): OA is a severe pathological condition causing significant pain
and stiffness in the joints. It is often characterized by the degradation of articular cartilage
and inflammation in the joints [145]. Ma et al. have demonstrated that inflamed chondro-
cytes show a higher expression of miR-10a, which targets the homeobox gene HOXA1,
resulting in chondrocyte apoptosis [146]. Treatment with the miR-10a antagonist is shown
to reduce chondrocyte apoptosis, while agomiR-10a hastens it [146]. Moreover, silencing
HOXA1 reverses the rescuing effect of the miR-10a antagonist against chondrocyte apop-
tosis [146]. These observations suggest that miR-10a and HOXA1 could be used as thera-
peutic targets against OA. Li et al. showed that higher miR-10a expression in inflamed
chondrocytes leads to the down-regulation of its other target, HOXA3, which results in
chondrocyte apoptosis and inhibition of their proliferation [147]. The treatment with the
miR-10a inhibitor increases the survivability of the inflamed chondrocytes, but HOXA3
silencing interferes with the rescuing effect of antagomiR-10a [147]. These observations
suggest that targeting miR-10a could be successfully used as a therapeutic approach to
treat OA [147]. miR-10a may also serve as a negative regulator during osteoblast
Figure 5. Various inflammation-associated diseases regulated by miR-10a.
miR-10a is a key regula-
tory molecule that influences several inflammation-associated diseases, such as rheumatoid arthritis
(RA), inflammatory bowel disease (IBD), colitis, acute pancreatitis (AP), sepsis, atherosclerosis,
and cancer.
Osteoarthritis (OA):
OA is a severe pathological condition causing significant pain
and stiffness in the joints. It is often characterized by the degradation of articular car-
tilage and inflammation in the joints [
145
]. Ma et al. have demonstrated that inflamed
chondrocytes show a higher expression of miR-10a, which targets the homeobox gene
HOXA1, resulting in chondrocyte apoptosis [
146
]. Treatment with the miR-10a antagonist
is shown to reduce chondrocyte apoptosis, while agomiR-10a hastens it [
146
]. Moreover,
silencing HOXA1 reverses the rescuing effect of the miR-10a antagonist against chondrocyte
apoptosis [
146
]. These observations suggest that miR-10a and HOXA1 could be used as
therapeutic targets against OA. Li et al. showed that higher miR-10a expression in inflamed
chondrocytes leads to the down-regulation of its other target, HOXA3, which results in
chondrocyte apoptosis and inhibition of their proliferation [
147
]. The treatment with the
miR-10a inhibitor increases the survivability of the inflamed chondrocytes, but HOXA3
silencing interferes with the rescuing effect of antagomiR-10a [
147
]. These observations
suggest that targeting miR-10a could be successfully used as a therapeutic approach to treat
OA [
147
]. miR-10a may also serve as a negative regulator during osteoblast differentiation
of human bone marrow mesenchymal stem cells and may be employed in the treatment of
bone repair in osteogenic-associated diseases [148].

Int. J. Mol. Sci. 2022,23, 15479 13 of 27
Table 4. The role of miR-10a in various inflammation-associated diseases.
Disease Cell Type Expression Target(s) Function Reference(s)
Rheumatoid
arthritis (RA) FLSs Down IRAK4,TAK1
β-TrCP, MAP3K7 Induces inflammation [126]
Inflamed
synoviocytes Down TBX5 Promotes proliferation, inhibit
apoptosis [143]
Osteoarthritis Inflamed
chondrocytes Up HOXA1 Induces apoptosis [146]
Inflamed
chondrocytes Up HOXA3 Induces apoptosis, inhibit
proliferation [147]
Inflammatory
bowel disease
(IBD)
Inflamed
intestinal
mucosal DCs
Down IL-12, IL-23p40,
NOD2 Induces inflammation [125]
Colitis
Intestinal
epithelial and
DCs
Down IL-12, IL-23p40 Induces inflammation [123]
Atherosclerosis ECs Down HOXA1, β-TrCP,
MAP3K7 Induces inflammation [122]
Sepsis ECs Up IRAK4, β-TrCP,
MAP3K7 Prevents inflammation [149]
ECs Up TAK1 Prevents inflammation, inhibit
vascular permeability [127,150]
Cancer
CD34+
mononuclear
cells of CML
Down USF2 Promotes cell growth [151]
Neuroblastoma Up NCOR2 Promotes cell growth, induce
differentiation [128]
Abbreviations: FLSs, fibroblast-like synoviocytes; DCs, dendritic cells; ECs, endothelial cells; CML, chronic
myeloid leukemia.
Inflammatory bowel disease (IBD):
IBD is another inflammation-associated disease
that involves chronic inflammation of the tissues in the digestive tract [
152
]. In the inflamed
mucosa of IBD patients, miR-10a expression is shown to be down-regulated [
125
]. This
was believed to be responsible for the increased expression of the target genes IL-12/IL-
23p40/NOD2 and prolonged intestinal inflammation [
125
]. The administration of anti-TNF
mAb was shown to increase miR-10a expression and down-regulate IL-12/IL-23p40/NOD2,
thereby inhibiting the function of Th1 and Th17 cells to control chronic inflammation in the
intestine [
125
]. miR-10a is also shown to be expressed in the epithelial and dendritic cells
in the intestine and helps maintain intestinal homeostasis. Commensal bacteria are shown
to down-regulate the expression of miR-10a in intestinal dendritic cells via TLR signaling
through the MyD88 pathway [
123
]. The down-regulation of miR-10a is accompanied by the
induction of miR-10a target genes IL-12/IL-23p40 and colitis in mice [
123
]. Thus, miR-10a,
whose aberrant expression plays a crucial role in the IBD pathogenesis, could be used as a
biomarker for the IBD.
Acute pancreatitis (AP):
AP, another type of inflammatory disease, is characterized
by an inflamed pancreas over a short period [
153
]. In AP patients, miR-10a levels in the
serum are found to be significantly down-regulated as compared to healthy controls and
thus could be used as a biomarker for AP [124].
Atherosclerosis:
Atherosclerosis, an inflammation-associated disease [
154
], is caused
by the thickening of arteries due to plaque deposition in the inner arterial wall [
155
].
Several inflammatory signaling pathways promote thrombosis, which is responsible for
atherosclerotic complications associated with stroke and myocardial infarction [
154
]. Fang
et al. observed a significantly lower expression of miR-10a levels in the regions of the

Int. J. Mol. Sci. 2022,23, 15479 14 of 27
inner aortic arch and aortic renal branches, which are susceptible to atherosclerosis [
122
].
HOXA1 expression, the target of miR-10a, was found to be significantly higher in those
athero-susceptible regions [
122
]. Moreover, the expression of two key miR-10a targets,
MAP3K7 and
β
-TrCP, were shown to be up-regulated in miR-10a knocked-down human
aortic endothelial cells and accompanied by the up-regulation of pro-inflammatory NF-
κ
B
signaling pathway and the release of pro-inflammatory cytokines, IL-6, IL-8, MCP-1, and
VCAM-1 [
122
]. The up-regulation of MAP3K7 and
β
-TrCP and induction of the NF-
κ
B
pathway were observed in the athero-susceptible regions of the endothelium [
122
]. Overall,
the above data indicate that miR-10a could be a potential biomarker for atherosclerosis
and targeting miR-10a could be a potential therapeutic approach to limit inflammation
associated with atherosclerosis.
Cancer:
Inflammation and cancer are intrinsically related. The development and
progression of cancer often lead to several inflammatory responses [
156
]. Targeting in-
flammation proves to be an attractive therapeutic approach for cancer prevention [
156
]. A
growing body of evidence indicates that miR-10a expression is de-regulated in different
types of cancer. A down-regulation of miR-10a is observed in several hematological cell
lines [
157
], CD34
+
acute [
158
], and chronic [
151
] myeloid leukemia cells. In addition, head
and neck squamous cancer cells exhibit a lower expression of miR-10a [
159
]. In contrast,
hepatocellular carcinoma stem cells are enriched with miR-10a [
129
,
160
]. In neuroblastoma
cells, retinoic acid treatment induces the expression of miR-10a, which targets nuclear re-
ceptor corepressor 2 (NCOR2) [
128
]. The down-regulation of NCOR2 promotes the growth
and differentiation of the neuroblastoma cells [
128
]. In many cases, miR-10a was shown to
be up-regulated in cancer cells, reflecting its role in oncogenic transformation [
161
–
164
].
Although aberrant miR-10a expression is observed in different types of cancer, it is unclear
at present whether its relative expression could serve as a biomarker for cancer.
14. Intercellular Transfer of miR-10a via Extracellular Vesicles (EVs):
Functional Implications
EVs are cell-secreted, membrane-enclosed, heterogenous bodies, which play a central
role in intercellular communication [
165
]. miRNAs are often known to be selectively
packaged into the EVs by the secreting cells [
166
]. The advancement of single-cell EVs and
single-cell EV analysis coupled with miRNA sequencing that provides a better picture of
the heterogeneity of the miRNA population in the EVs helps in understanding different
phenotypic effects of distinct EV populations [
167
,
168
]. Accumulating evidence indicates
that EVs actively transport miRNAs between cells, thereby influencing the phenotypes
of the target recipient cells [
169
]. EVs-associated miRNAs often serve as biomarkers in
several disease conditions, such as asthma [
170
], traumatic brain injury [
171
], respiratory
diseases [
172
], kidney diseases [
173
], cardiovascular diseases [
174
], cancer [
175
], liver
disease [176], and diabetic neuropathy [177].
Recent studies showed that EVs released from vascular endothelium (EEVs) are en-
riched with miR-10a, and the EEVs could deliver miR-10a to recipient cells and alter their
phenotype by down-regulating the miR-10a target genes in recipient cells [
127
,
149
]. Njock
et al. showed that EEVs suppress monocytic activation by inhibiting pro-inflammatory re-
sponses and up-regulating immunomodulatory responses via the transfer of miR-10a [
149
].
EEVs-mediated transfer of miR-10a was shown to down-regulate the expression of several
genes in the NF-
κ
B signaling pathway, such as MAP3K7,
β
-TrCP, and IRAK4, in recipient
monocytes, and thus suppress their activation [
149
]. Recent studies from our laboratory
indicate that vascular endothelium releases EVs into the circulation in response to a coagula-
tion protease, factor VIIa (FVIIa), via endothelial cell protein C receptor (EPCR)-dependent
activation of protease-activated receptor 1 (PAR1)-mediated cell signaling [
178
]. In a con-
tinuation study, Das et al. demonstrated that the expression of miR-10a is increased in
endothelial cells after challenging with FVIIa [
127
]. FVIIa-released EEVs contain signifi-
cantly higher levels of miR-10a as compared to EEVs released under basal conditions [
127
].
The uptake of FVIIa-EEVs but not control-EEVs by monocytes or naïve endothelial cells

Int. J. Mol. Sci. 2022,23, 15479 15 of 27
confers anti-inflammatory or vascular protective properties, respectively, to these cell
types [
127
]. The incorporation of anti-miR-10a into the FVIIa-released EEVs removes the
EEVs’ cytoprotective responses, indicating the crucial role of miR-10a in mediating the
cytoprotective responses of FVIIa-released EEVs [127].
Additional studies showed that FVIIa-EEVs-mediated delivery of miR-10a to mono-
cytes down-regulates LPS-induced pro-inflammatory responses in monocytes by tar-
geting TAK1 and down-regulating the activation of the NF-
κ
B signaling pathway (see
Figure 6) [127].
The transfer of miR-10a by FVIIa-EEVs to endothelial cells imparted barrier
protective responses against LPS by restoring the expression of the tight junction protein
ZO-1 [
127
]. Consistent with these
in vitro
observations, Das et al. also showed that FVIIa
administration in mice increased the levels of circulating EEVs laden with miR-10a, and
these EEVs imparted cytoprotective responses in ex vivo cell model systems [
127
]. Alter-
natively, the administration of FVIIa-EEVs but not control EEVs generated from cultured
murine endothelial cells protected mice against LPS-induced inflammation and barrier
disruption [
127
]. In a further study, the same group reported that FVIIa infusion into
hemophilia patients increases the level of circulating EEVs in the plasma, and these EEVs
contain elevated levels of miR-10a [
150
]. The fusion of FVIIa-EEVs with recipient cells
resulted in an anti-inflammatory phenotype in monocytes and barrier-protective responses
in endothelial cells, and the transfer of miR-10a to recipient cells was responsible for these
protective effects [150].
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 16 of 28
laboratory indicate that vascular endothelium releases EVs into the circulation in response
to a coagulation protease, factor VIIa (FVIIa), via endothelial cell protein C receptor
(EPCR)-dependent activation of protease-activated receptor 1 (PAR1)-mediated cell sig-
naling [178]. In a continuation study, Das et al. demonstrated that the expression of miR-
10a is increased in endothelial cells after challenging with FVIIa [127]. FVIIa-released
EEVs contain significantly higher levels of miR-10a as compared to EEVs released under
basal conditions [127]. The uptake of FVIIa-EEVs but not control-EEVs by monocytes or
naïve endothelial cells confers anti-inflammatory or vascular protective properties, re-
spectively, to these cell types [127]. The incorporation of anti-miR-10a into the FVIIa-re-
leased EEVs removes the EEVs’ cytoprotective responses, indicating the crucial role of
miR-10a in mediating the cytoprotective responses of FVIIa-released EEVs [127].
Additional studies showed that FVIIa-EEVs-mediated delivery of miR-10a to mon-
ocytes down-regulates LPS-induced pro-inflammatory responses in monocytes by target-
ing TAK1 and down-regulating the activation of the NF-κB signaling pathway (see Figure
6) [127]. The transfer of miR-10a by FVIIa-EEVs to endothelial cells imparted barrier pro-
tective responses against LPS by restoring the expression of the tight junction protein ZO-
1 [127]. Consistent with these in vitro observations, Das et al. also showed that FVIIa ad-
ministration in mice increased the levels of circulating EEVs laden with miR-10a, and
these EEVs imparted cytoprotective responses in ex vivo cell model systems [127]. Alter-
natively, the administration of FVIIa-EEVs but not control EEVs generated from cultured
murine endothelial cells protected mice against LPS-induced inflammation and barrier
disruption [127]. In a further study, the same group reported that FVIIa infusion into he-
mophilia patients increases the level of circulating EEVs in the plasma, and these EEVs
contain elevated levels of miR-10a [150]. The fusion of FVIIa-EEVs with recipient cells
resulted in an anti-inflammatory phenotype in monocytes and barrier-protective re-
sponses in endothelial cells, and the transfer of miR-10a to recipient cells was responsible
for these protective effects [150].
Figure 6. Schematic representation showing the release of miR-10a-loaded EVs from the endothelial
cells and their uptake by target recipient cells to alter their phenotypic responses. FVIIa binds to
EPCR on endothelial cells and activates PAR1 by proteolytic cleavage at the R41 site. The activation
of PAR1 leads to the induction of miR-10a expression in the cells. PAR1 activation also triggers the
release of EVs from the endothelial cells, and the FVIIa-EEVs are packaged with miR-10a. The EEVs
are taken up by the target recipient cells (such as monocytes or naïve endothelial cells) via endocy-
tosis, and the release of miR-10a from the vesicles into the recipient cell’s cytosol results in the down-
Figure 6.
Schematic representation showing the release of miR-10a-loaded EVs from the endothelial
cells and their uptake by target recipient cells to alter their phenotypic responses. FVIIa binds to EPCR
on endothelial cells and activates PAR1 by proteolytic cleavage at the R41 site. The activation of PAR1
leads to the induction of miR-10a expression in the cells. PAR1 activation also triggers the release of
EVs from the endothelial cells, and the FVIIa-EEVs are packaged with miR-10a. The EEVs are taken
up by the target recipient cells (such as monocytes or naïve endothelial cells) via endocytosis, and the
release of miR-10a from the vesicles into the recipient cell’s cytosol results in the down-regulation of
the target gene’s TAK1 expression. TAK1 down-regulation impairs LPS-induced activation of the
NF-
κ
B signaling pathway and the concomitant induction of pro-inflammatory cytokines, TNF-
α
,
IL-1
β
, and IL-6, as well as tight junction protein ZO-1, thereby limiting LPS-induced inflammation
and vascular permeability in the recipient cells.

Int. J. Mol. Sci. 2022,23, 15479 16 of 27
15. Atypical Functions of miR-10a
miR-10a is considered to be one of the important regulators in protein synthesis as it
induces the translation of 5’-terminal oligopyrimidine (TOP) mRNAs [
59
]. The TOP mRNAs
encode proteins such as ribosomal proteins (RPs), which regulate protein synthesis [
179
].
miR-10a overexpression shows a ~30% induction in protein synthesis, whereas its inhibition
decreases protein synthesis by ~40% in murine embryonic stem cells [
59
]. The binding site
of miR-10a for TOP mRNAs is located at the 5’-UTR rather than the conventional 3’-UTR
position of the mRNAs, and hence is considered to be atypical [
59
]. Another unconventional
function of miR-10a is the inhibition of HOXD4 transcription via DNA methylation [
180
].
miR-10a overexpression is found to increase the level of the repressive H3K27me3 epigenetic
histone modification on the HOXD4 promoter, leading to the transcriptional up-regulation
of the HOXD4 gene [180].
16. miRNAs in Immune Cell Development and Function
miRNAs are known to regulate the function of different cells in the immune system.
T-cells:
Mature peripheral T cells are mainly comprised helper T cells (CD4
+
T cells),
cytotoxic T cells (CD8
+
T cells), and regulatory T cells (T
reg
cells) [
181
], and miRNAs are
shown to be involved in the development of functional peripheral T cell subsets. For
example, miR-142 binds to the 3’-UTR of glycoprotein A repetitions predominant (GARP)
mRNA, and by down-regulating GARP expression suppresses the proliferation of CD25
+
helper T cells [
182
]. In helper T cells, miR-29 is known to downregulate the T helper type 1
activation in response to intracellular pathogens by targeting IFN-γ[183].
Numerous miRNAs, such as miR-150, miR-155, and let-7 family miRNAs, are involved
in the development of effector- or central-memory cells from activated CD8
+
T cells, driven
by the function of IL-2 or IL-15 [
184
]. In particular, miR-150 targets K (+) channel interacting
protein 1 (KChIP.1) in developing central-memory T cells, and the up-regulation of KChIP.1
determines the fate of CD8+T cells to central-memory T cells [184].
miR-10a is known to play a pivotal role in differentiating T
reg
cells. The expression
of miR-10a is induced by transforming growth factor-
β
(TGF-
β
) or retinoic acid, which
restricts the T
reg
differentiation into follicular helper T cells via targeting transcriptional
suppressor Bcl-6 and co-suppressor Ncor2 [
185
]. miR-146a is usually over-expressed in
T
reg
cells, but its deficiency often leads to the augmented expression of its target gene signal
transducer and activator transcription 1 (Stat1), thereby resulting in the dysregulation of
IFN-γresponses and breakdown of immune tolerance [186].
Dendritic cells:
Several miRNAs are also known to be associated with the develop-
ment and differentiation of dendritic cells (DCs). For example, miR-142 is highly expressed
in DCs, and its deficiency results in the impairment of DCs’ development and their differ-
entiation from bone marrow (BM) stem cells [
187
]. miR-22 acts as a negative regulator of
DCs’ differentiation, probably via the down-regulation of its target gene, IRF8 (interferon
regulatory factor 8) expression [
188
]. miR-21 and miR-34a play pivotal roles in human
monocyte-derived DCs (MDDCs) differentiation, and the inhibition of miR-21 or miR-34a
stalled MDDCs differentiation via the up-regulation of their targets, WNT1 and JAG1 [
189
].
B cells:
miRNAs often modulate the development of B cells. For example, the miR-
17-92 cluster, which comprises six single mature miRNAs (miR-17, -18a, -19a, -20a, -19b-1,
and -92a-1) and two paralogs (miR-106a~363 and miR-106b~25) [
27
], plays important roles
in fetal and adult BM B cell development. B cell development in miR-17-92-deficient mice
is perturbed at the pro- and pre-B cell differentiation stages via the modulation of the
pro-apoptotic protein Bim expression [
190
]. Constitutive expression of miR-34a inhibits
the pro-B cell to pre-B cell transition via down-regulating the expression of Foxp1, thereby
perturbing the maturation of B cells [
191
]. miRNAs also regulate the development of B cells
in peripheral B cell maturation stages. The development of marginal zone B cells (MZB)
from immature B cells in the spleen was suppressed in miR-146a deficient mice through
inhibition of the Notch2 pathway that directly targets Numb [
192
]. miR-125b, on the other

Int. J. Mol. Sci. 2022,23, 15479 17 of 27
hand, perturbs B cell differentiation into plasma cells in the germinal center via targeting
transcription factors IRF4 and BLIMP-1 [193].
17. miRNAs in Pregnancy-Related Diseases
Several pregnancy-associated diseases, such as preeclampsia (PE), HELLP (hemol-
ysis, elevated liver enzymes, and low platelet count) syndrome, and diabetes, are often
characterized by an enhanced inflammatory response, and miRNAs play vital roles in the
development of these diseases. Hromadnikova et al. observed an elevated level of circu-
lating C19MC miRNAs, such as miR-516-5p, miR-517, miR-520a, miR-525, and miR-526a,
in the plasma of PE patients [
194
]. In another study, Hromadnikova et al. reported the
up-regulation of miR-17-5p, miR-20b-5p, miR-29a-3p, and miR-126-3p in the plasma of
PE patients with gestational hypertension (GH) [
195
]. Biro et al., by system biology tool
approaches, identified miR-210 in the pathogenesis of PE [
196
]. The same group has ob-
served an increase in miR-210 levels in the circulating plasma exosomes of PE patients [
197
].
The levels of miR-122, miR-758, and miR-133a were also shown to be up-regulated in the
maternal sera of patients suffering from HELLP syndrome [
198
]. miR-16-5p, miR-142-3p,
and miR-144-3p are also shown to be up-regulated in the sera of women with gestational
diabetes mellitus (GDM) and could serve as biomarkers for GDM [199].
18. Conclusions and Future Directions
A growing body of evidence from the past two decades indicates that miRNAs not
only regulate host immune responses but also modulate several inflammatory pathways.
Some miRNAs are known to produce pro-inflammatory effects, whereas others impart
anti-inflammatory potential. In either case, they play a major role in pathophysiological
conditions. Inflammatory miRNAs drive the expression of inflammatory cytokines, which
recruit the immune cells necessary for the immune clearance of pathogens. On the other
hand, anti-inflammatory miRNAs mediate anti-inflammatory effectsthat are essential for
the post-pathogen clearance healing process. Therefore, a balance between pro- and
anti-inflammatory responses is required to maintain homeostasis in the system in which
miRNAs play crucial roles. Due to their stable expression in the blood and the high
efficiency of methods to measure their abundance, miRNAs can be considered a promising
diagnostic tool for predicting the severity of inflammatory responses. Understanding
their mechanism of action will aid in developing new therapeutic strategies to control the
pathogenesis of the inflammatory disease. Targeting several miRNAs by the administration
of miRNA inhibitors (anti-miRNAs) or miRNA mimics could be one of the most valuable
therapeutic strategies to control miRNA-target gene expression and regulate the associated
inflammatory dysregulation. The prime advantage of miRNA-based therapies as compared
to other gene/protein-based approaches is that the sequences are easy to synthesize, and
a few minor modifications make the sequences stable and resistant to degradation inside
the biological system. Another advantage is that the multiple target specificity of a single
miRNA makes them more effective in controlling disease outcomes than individual gene
regulation. Special caution should be exercised in developing and using miRNA-based
therapies, as too much inhibition or over-expression may lead to unintended pathological
abnormalities. Despite this or any other limitations, we anticipate that the miRNA-based
strategies should be highly useful in diagnosing and treating different acute and chronic
inflammatory diseases.
Author Contributions:
K.D. contributed to the conceptualization, literature search, experimental
data collection, and study design and wrote the initial draft of the manuscript. L.V.M.R. contributed
to the conceptualization, critical reviewing, and editing of the final version of the manuscript. All
authors have read and agreed to the published version of the manuscript.

Int. J. Mol. Sci. 2022,23, 15479 18 of 27
Funding:
This work was supported by grants from the National Institute of Health (HL124055,
AI163558, and AI163608) and endowment funds from The Dr. and Mrs. James Vaughn Professorship
in Biomedical Research (L.V.M.R.). K.D. received the Judith Graham Pool Post-Doctoral Fellowship
Award from the National Hemophilia Foundation.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments:
The authors thank Christian De Jong for editing the manuscript for the En-
glish language.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
ncRNA non-coding RNA
miRNA microRNA
siRNA short interfering RNA
piRNA Piwi-interacting RNA
DGCR8 diGeorge Syndrome Critical Region 8
AGO Argonaute
m7G 7-methylguanosine
shRNA short hairpin RNA
miRISC miRNA-induced silencing complex
PABPC poly(A)-binding protein C
DCP2 decapping protein 2
FXR1 fragile-x-mental retardation-related protein 1
ARE AU-rich element
TNF-αtumor necrosis factor-α
LPS lipopolysaccharide
IL interleukin
PAN poly(A) nuclease
CCR4 carbon catabolite repression 4
NOT negative on TATA-less
XRN1 eXoRiboNuclease
MyD88 myeloid differentiation primary response 88
TRIF TIR (Toll/interleukin-1 receptor) domain-containing adapter-inducing interferon-β
EC endothelial cell
EV extracellular vesicle
Zeb1 zinc finger E-box binding homeobox 1
MCP1 monocyte chemoattractant protein 1
NF-kB nuclear factor kappa B
JAK1 Janus kinase 1
STAT signal transducer and activator of transcription
IRF4 interferon regulatory factor 4
PPAR-γperoxisome proliferator-activated receptor gamma
TTP tristetraprolin
SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1
IBD inflammatory bowel disease
RA rheumatoid arthritis
SPRED1 Sprouty-related EVH1 domain-containing protein 1
PIK3R2 phosphoinositol-3 kinase regulatory subunit 2
VCAM1 vascular cell adhesion molecule 1
SCI spinal cord injury
TACE tumor necrosis factor alpha converting enzyme
TRAF6 tumor necrosis factor receptor-associated factor 6

Int. J. Mol. Sci. 2022,23, 15479 19 of 27
MAPK mitogen-activated protein kinase
DR6 death receptor 6
Chi3l1 chitinase 3-like 1
TAK1 transforming growth factor-β(TGF-β)-activated kinase 1
TLR4 toll-like receptor 4
IKK inhibitor of nuclear factor-κB (IκB) kinase
IRAK interleukin-1 receptor-associated kinase
MKP5 mitogen-activated protein (MAP) kinase phosphatase 5
AP acute pancreatitis
HOX homeobox
TWIST1 twist-related protein 1
DNMT DNA methyltransferase
FLSs fibroblast-like synoviocytes
β-TrCP β-transducin repeat-containing protein
MAP3K7 mitogen-activated protein 3 kinase7
TBX5 T-box transcription factor 5
OA osteoarthritis
NOD2 nucleotide-binding oligomerization domain-containing 2
Th T-helper
FVIIa factor VIIa
TOP 5’-terminal oligopyrimidine
RPs ribosomal proteins
FADD Fas-associated death domain
Ripk1 receptor-interacting serine/threonine-protein kinase 1
KLF4 Krüppel-like factor 4
VSMC vascular smooth muscle cell
LGR4 Leucine Rich Repeat Containing G Protein-Coupled Receptor 4
GP130 glycoprotein 130
IL17R IL17 receptor
IL17RA IL17 receptor A
CD Crohn’s disease
UC ulcerative colitis
AAA abdominal aortic aneurysm
DN diabetic nephropathy
MMP matrix metalloproteinase
KBTBD7 Kelch repeat and BTB (bric-a-brac) domain-containing 7
DAMPs damage-associated molecular patterns
MI myocardial infarction
DC dendritic cell
CML chronic myeloid leukemia
USF2 upstream transcription factor 2
NCOR2 nuclear receptor corepressor 2
CD34+cluster of differentiation 34 positive
Yin Yang 1 YY1
Treg T regulatory cell
GARP glycoprotein A repetitions predominant
KChIP.1 potassium Voltage-Gated Channel Interacting Protein 1
BM bone marrow
WNT Wingless-related integration site
JAG1 jagged 1
MZB marginal zone B cell
GC gastric cancer
PAK1 p21-activated kinase 1
FAK focal adhesion kinase
EMT epithelial to mesenchymal transition
CSC cancer stem cell
SET8 SET domain-containing (lysine methyltransferase) 8

Int. J. Mol. Sci. 2022,23, 15479 20 of 27
PA28 proteasome activator 28
EGFR extracellular growth factor receptor
PAX6 paired box protein 6
IGF1 insulin-like growth factor 1
LVH left ventricular hypertrophy
PDGF platelet-derived growth factor
CHD coronary heart disease
CS cardiac sarcoidosis
DE diabetic embryopathy
PE preeclampsia
HELLP hemolysis, elevated liver enzymes, and low platelet count
GH gestational hypertension
GDM gestational diabetes mellitus
BLIMP-1 B lymphocyte-induced maturation protein 1
LC lung cancer
BC breast cancer
HC hepatocellular carcinoma
CVD cardiovascular disease
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