Functional crosstalk between Long non-coding RNAs and the NLRP3 inflammasome in the regulation of diseases

Abstract

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are involved in various pathophysiological processes of disease, such as cancer occurrence, viral invasion, and inflammatory damage. The main inflammatory body component, nod-like receptor protein 3 (NLRP3), is the trigger point of inflammatory reactions and inflammation-related diseases and coordinates the body's response to inflammation. At present, increasing evidence shows that the interaction of lncRNAs and the NLRP3 inflammasome plays an important role in the inflammatory response and different diseases. This may be involved in the development and progression of various diseases by activating signalling pathways and a variety of molecular regulatory mechanisms—this article reviews progress in research on the relationship between lncRNAs and the NLRP3 inflammasome under different conditions.

Full text

Molecular Immunology 131 (2021) 191–200
Available online 11 January 2021
0161-5890/© 2021 Elsevier Ltd. All rights reserved.
Review
Functional crosstalk between Long non-coding RNAs and the NLRP3
inammasome in the regulation of diseases
Deqiang Luo
a
,
b
, Fen Liu
a
, Jianguo Zhang
a
, Qiang Shao
a
, Wenqiang Tao
a
, Rui Xiao
a
, Wei Dai
b
,
Kejian Qian
a
,
*
a
Department of Intensive Care Unit, The First Afliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Dong Lake District, Nanchang, Jiangxi Province,
330000, China
b
Department of Intensive Care Unit, the Fifth People’s Hospital of Shangrao City, No. 1 Jiannan Road, Xin Zhou District, Shangrao 334000, China
ARTICLE INFO
Keywords:
Inammatory inammasome
Inammatory diseases
NLRP3
Long-chain non-coding RNA
ABSTRACT
Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are involved in various pathophysio-
logical processes of disease, such as cancer occurrence, viral invasion, and inammatory damage. The main
inammatory body component, nod-like receptor protein 3 (NLRP3), is the trigger point of inammatory re-
actions and inammation-related diseases and coordinates the body’s response to inammation. At present,
increasing evidence shows that the interaction of lncRNAs and the NLRP3 inammasome plays an important role
in the inammatory response and different diseases. This may be involved in the development and progression of
various diseases by activating signalling pathways and a variety of molecular regulatory mechanisms—this
article reviews progress in research on the relationship between lncRNAs and the NLRP3 inammasome under
different conditions.
1. Introduction
Inammation underlies numerous pathological processes involving
the action of various inammatory cells and inammatory activating
factors and serves as the body’s initial adaptive response to external
stimuli, stress, tumours, metabolic diseases, and allergies(Medzhitov,
2008, 2010). Long noncoding RNAs (lncRNAs) do not encode any pro-
teins longer than 200 nucleotides and were previously regarded as
non-functional molecular noise RNA(Gutschner and Diederichs, 2012;
Mendell et al., 2004). However, certain annotated lncRNAs that bind to
ribosomes and contain a translation region that can translate peptides
have gradually been discovered(Nam et al., 2016). LncRNAs regulate
related genes by directly or indirectly binding to specic DNA/RNA or
protein sites in the cytoplasm or nucleus(Moura et al., 2014). In contrast
to miRNAs and circRNAs, lncRNAs have well-conserved sequences and
structures and cannot participate in various regulatory mechanisms
(Kornfeld and Brüning, 2014). In different biological environments, they
perform particular functions and regulate complex natural mechanism;
e.g., acting (i) as scaffolds to polymerize protein complexs, (ii) as
molecular sponges for ceRNA protagonists, (iii) as host genes of various
RNAs (iv) to guide the mRNA degradation process, and isolate of tran-
scription factors for DNA regulation and epigenetic regulation of chro-
matin conformation, and (v) as protectors of mRNA through the
prevention of degradation by binding miRNA(Hadjicharalambous and
Lindsay, 2019; Kornfeld and Brüning, 2014; Morlando and Fatica,
2018). Larg high-quality sequencing platform data sets have indicated
that the emergence of many inammatory genes and the activation of
signalling pathways found abnormal lncRNA expression (Liao et al.,
2018). Pyridine-containing domain 3 (NLRP3), also called the inam-
masome, is a multimolecular protein complex that performs a specic
function for the cytoplasm in the host’s innate immunity by secreting
inammatory factors and promoting maturation, such as for inter-
leukin-1β (IL-1β) and interleukin-18 (IL-18)(He et al., 2016a; Zhou et al.,
2011). Seasonable activation of the NLRP3 inammasome has a positive
effect on the body; excessive activation of the NLRP3 inammasome
causes programmed cell death termed ‘pyroptosis’ via the secretion of
large amounts of proinammatory cytokines and triggers a highly in-
ammatory form of caspase-1(Van Opdenbosch and Lamkan, 2019).
* Corresponding author at: Department of Intensive Care Unit, The First Afliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Dong Lake
District, Nanchang City, Jiangxi Province, 330000, China.
E-mail addresses: yydlt@163.com (D. Luo), 807792302@qq.com (F. Liu), drzhangjianguo@163.com (J. Zhang), 372661438@qq.com (Q. Shao), twqnc@139.com
(W. Tao), 421583336@qq.com (R. Xiao), 415556881@qq.com (W. Dai), ndyfyicu@email.ncu.edu.cn (K. Qian).
Contents lists available at ScienceDirect
Molecular Immunology
journal homepage: www.elsevier.com/locate/molimm
https://doi.org/10.1016/j.molimm.2020.12.038
Received 2 May 2020; Received in revised form 22 November 2020; Accepted 30 December 2020

Molecular Immunology 131 (2021) 191–200
192
There are usually two signal modes of NLRP3 inammasome activation:
the host’s crucial immune response to external stimuli regulates the
main checkpoints of the two signalling pathways(He et al., 2016a;
Swanson et al., 2019). A recent explosion in studies on the regulation of
the interaction between lncRNAs and the NLRP3 inammasome in the
activation of inammatory pathways has brought to the forefront new
insights into the prophylaxis, diagnosis, and treatment of various dis-
eases(Bordon, 2019; Haque et al., 2020; Ma et al., 2019; Nie et al., 2019;
Song et al., 2019a; Zhang et al., 2020a). Our article reviews recent
high-throughput studies of the relationship between lncRNAs and
NLRP3 inammasome under different conditions.
2. The molecular structure and biological function of lncRNAs
and the NLRP3 inammasome
2.1. The molecular structure and the role of lncRNAs
LncRNAs are poorly conserved and lack complete ORFs, longer than
200 nt(Quinn and Chang, 2016). As with messenger RNA (mRNA),
transcription for most lncRNAs is mediated by RNA polymerase II; this
transcription mechanism is completed by 5-terminal capping, Pol II
occupancy, histone modications, and polyadenylation. RNA polymer-
ase III can mediate part of lncRNA transcription(Pagano et al., 2007).
The traditional understanding regards lncRNAs as having no coding
function and being more poorly conserved than mRNAs, but they have
been shown to exert a productive regulatory function(Pagano et al.,
2007). Many different levels of lncRNA structure play specic roles in
every level of gene expression in particular environments. The
well-known star molecule nuclear lncRNA MALAT1 has a standard
genomic structure; RNA polymerase II regulates MALAT1 to form a
transcript-like 3′end of a tRNA-like structure. Although no functional
units can be found in the primary structure of lncRNAs, there are many
hairpin structures in their sublevel construction. For example, lncRNA
SPRY4-IT1 originates from an intron of the SPRY4 gene, whose sec-
ondary structure is highly conserved in melanocytoma(Khaitan et al.,
2011). Therefore, we should gradually shift the dogma concept of mo-
lecular biology to lncRNAs, which only encode proteins. LncRNAs
participate in the regulation of protein-coding and epigenetic genes by
controlling processes such as RNA epigenetic modications, transcrip-
tional gene silencing, and posttranscriptional gene regulation(Martens
et al., 2004)(Fig. 1)(Salviano-Silva et al., 2018). LncRNAs suppress gene
transcription and expression by acting on encoding genes upstream or
downstream of promoter regions by various mechanisms, such as
interfering with RNA binding sites or as transcription factors that
interact with sequence-matching promoters of mRNA (Engreitz et al.,
2016a). LncRNAs also alter DNA structure and its transcription mech-
anisms through DNA methylation, the formation of protein trimers, and
heterochromatin formation, leading to suppressor disease gene silencing
(Wu et al., 2015b; Zhou et al., 2015). On the other hand, lncRNAs inhibit
the expression of disease-associated genes by targeting mRNA
Fig. 1. Long noncoding RNAs (lncRNAs) genomic diversity location relative to protein-coding genes and regulatory mechanisms of lncRNAs in the various cellular
substructures. (A) Nomenclature of different lncRNA genes (purple ellipses) according to their genomic locations relative to nearby coding genes (blue curves) or
exons of coding genes (blue ovals). (B) The molecular mechanisms of lncRNAs: (B1) as a part of the Barr body of somatic cells, such as lncRNA Xist; (B2) as enhancer
RNAs, playing an RNA-mediated role in cis or in trans; (B3) as decoys to structural proteins, affecting their binding to DNA sites, such as remodelling transcription
factors inuencing chromatin structure; (B4) as molecular guided signals, regulating gene expression through signalling pathways; (B5) inducing chromatin
remodelling at specic genomic loci; (B6) as molecular scaffolds, assembling different proteins and forming new protein complexes, which regulate gene tran-
scription; (B7) regulating catalytic activity of enzymes (such as kinases) and modulating their signal pathways; (B8) forming new transcripts by splicing initial
transcripts; (B9) as molecular sponges competing for binding microRNAs (miRNAs), inhibiting their function; (B10) targeting proteins and forming new molecular
complexes that can change their subcellular location; (B11) binding messenger RNAs (mRNAs) and promoting their degradation to improve their function. In
addition, lncRNAs can (B12) produce results by transferring to other cells via extracellular vesicles (EVs).
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Molecular Immunology 131 (2021) 191–200
193
transcription factors or activating extra proteins to promote the
expression of target genes(Engreitz et al., 2016b). In addition, lncRNAs
also interact with mRNAs in the cytoplasm or nucleus by various bio-
logical regulatory mechanisms, such as by modulating their activity to
bind to small RNAs, affecting the chromatin structure as with chromo-
some circulation, and regulating subcellular localization (B¨
ohmdorfer
and Wierzbicki, 2015; Willingham et al., 2005).
2.2. The structure and function of the NLRP3 inammasome
2.2.1. The molecular structure of the inammasome
The NLRP3 inammasome is a protein whose gene contains nine
coding exons and located on chromosome 1q44. NLRP3 is found in the
cytoplasm, and is an essential component of the inammatory signalling
complex responding to microbes or external stimuli(Freeman et al.,
2017; Lamkan and Kanneganti, 2010). The well-known NLRP3
inammasome complex mainly includes three components: the ASC
adaptor, pro-caspase-1 effector, and NLRP3 receptor (Swanson et al.,
2019) (Fig. 2). As a tripartite protein, its core functional structure in-
cludes an amino-terminal pyrin domain (PYD), a central NACHT domain
(domain present in NAIP, CIITA, HET-E, and TP1), and a
carboxy-terminal leucine-rich repeat domain (LRR domain). NLRP3
self-association and function are closely related to the ATPase activity of
the NACHT domain(Duncan et al., 2007), which is thought to induce
autoinhibition. ASC contains two protein interaction domains: PYD and
the carboxy-terminal caspase recruitment domain (CARD). Caspase-1
has a sizeable central catalytic domain (p20), an amino-terminal
CARD, and a carboxy-terminal small catalytic subunit domain (p10).
Given stimulation, homotypic interactions between the NACHT domains
of NLRP3 are oligomerized (Fig. 1B). Next, the oligomeric NLRP3
interacting through PYD-PYD binding ASCs and nucleates helical ASC
lament formation. The familiar ASC speck is the coalescence of mul-
tiple ASC laments into a single macromolecular focal point(Lu et al.,
2014; Schmidt et al., 2016). Assembled ASCs enable proximity-induced
caspase-1 self-cleavage and activation after recruiting caspase-1 through
CARD–CARD interactions. Caspase-1 can increase proteolytic activity
after binding on the p33 - p10 complex generated from ASC self--
cleavage(Wang et al., 2019b). Through interaction between CARD and
p20, ASC releases the p20–p10 heterotetramer that terminates its
protease activity because it is unstable in cells (Wang et al., 2019b).
Recently, NIMA-related kinase 7 (NEK7), a known serine-threonine ki-
nase associated with mitosis, was found to play an essential role in
NLRP3 inammasome activation (He et al., 2016b). Only the inam-
masome sensor NLRC4 (including NOD, LRR, and CARD 4) and
interferon-inducing proteins AIM2, and NEK7 interact specically with
NLRP3. Under inammasome activation, the increased NEK7–NLRP3
interaction leads to the assembly of NEK7 and NLRP3 into a complex
that is essential for caspase-1 activation and ASC speck formation(Shi
et al., 2016). Therefore, NEK7 seems to be a unique core component of
the NLRP3 inammasome.
2.2.2. The signalling pathway of inammasome activation
The activity of NLRP3 can be regulated by carboxy-terminal LRR self-
inhibitory properties. NLRP3 can sense microbial ligands and endoge-
nous alarm proteins. (e.g., via the amino-terminal PYD domain of
NLRP3) and can allow complementary pairing with the PYD domain of
ASC, the core NACHT domain responsible for self-oligomerization
(Lamkan and Dixit, 2009). To date, we know that the NLRP3 inam-
masome performs molecular functions in the cytoplasm of multiple
mammalian cells, such as inammation and immune-related cells – T
cells and B cells, dendritic cells, monocytes, macrophages, granulocytes,
etc.(Ahmad et al., 2013; Dombrowski et al., 2011; Sandanger et al.,
2013). The assembly of the NLRP3 inammasome is triggered by a series
of internal and external activators, including PAMPs, such as dsRNA,
viral RNA, LPS, MDP, decomposition products of the cell wall compo-
nent peptidoglycan, and bacteria(Kanneganti et al., 2006; Xu et al.,
2013). In addition to the most studied PAMPs, the NLRP3 inammasome
is activated by diverse compounds, toxins, microorganisms, the
little-known maltoxin, and Nigerian toxic aerosols containing Bacillus
brevis(McCoy et al., 2010). There are two critical distinct activation steps
for the NLRP3 inammasome(Ozaki et al., 2015; Sutterwala et al., 2014;
Zhong et al., 2013) (Fig. 2). The rst step is NLRP3 inammasome
priming: nuclear factor kappa B (NF-κB) signalling is initially activated
when TLRs recognize many PAMPs or DAMPs, and then the priming
process can regulate the transcription of inactive NLRP3, pro-IL-1β, and
pro-IL-18(Bauernfeind et al., 2009; Franchi et al., 2012). This priming of
the NLRP3 inammasome is often induced by lipopolysaccharides in
Vetro(Park et al., 2015). The second step is the activation of the NLRP3
Fig. 2. A Two-Signal Activated Model for the
NLRP3 inammasome. Multiple microbial mol-
ecules or inammatory cytokines stimulate the
priming signal model (Model 1, left). The acti-
vation of NF-κB and subsequent increases in the
activity of NLRP3, caspase-1, pro-interleukin-1β
(pro-IL-1β), fas-mediated death domain protein
(FADD), etc., participate in the priming step by
regulating the NF-κB/NLRP3/IL-1β axis. Acti-
vation of the NLRP3 inammasome results in
multiple posttranslational modications and
interacting receptor ligands. The signal activa-
tion model (Model 2, right) is motivated by
various endogenous and exogenous stimuli,
including small RNA viruses, ATP, pore-forming
toxins, and particulate matter. The upregulation
of NLRP3 induces the activation of diverse
molecular and cellular signalling pathways,
including mitochondrial dysfunction, ionic ux,
reactive oxygen species (ROS) generation, and
lysosomal damage, which are involved in the
activation of the NLRP3 inammasome.
BRCA1/BRCA2, BRCC3-containing complex
subunit 3; JUN N-terminal kinase 1; IL-1R, IL-1β
receptor; JNK1, JUN N-terminal kinase 1; PKD,
protein kinase D; TLR, toll-like receptor; TNFR,
tumour necrosis factor receptor.
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Molecular Immunology 131 (2021) 191–200
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inammasome via ASC assembly, oligomerization, and binding with
pro-caspase-1 to form a complex by a different stimulus. Then, the
activated membrane sensor of the NLRP3 inammasome induces the
structural conversion of pro-caspase-1 to functional caspase-1, which
results in the secretion of a large number of inammatory end products
IL-18 and IL-1β(Kim et al., 2015; Ozaki et al., 2015). In recent years, it
has been recognized that the NLRP3 inammasome is regulated by
noncoding RNAs (miRNAs, lncRNAs, circRNAs, etc.) in the post-
transcriptional regulation of gene expression.
2.3. Pyroptosis and NLRP3
The inammasome secretes and induces the maturation of IL-1β/18,
and its activation triggers a form of inammatory cell death called
pyroptosis(Fig. 2). Cell rupture caused by pyroptosis also promotes
immature inammatory cytokines such as IL-1β(Heid et al., 2013).
IL-1β/18 and pyrokinesis initiate inammatory or anti-inammatory
effects in the body. More importantly, the release of IL-1β is indepen-
dent of the anti-inammatory effects of pyroptosis(Liu et al., 2016).
Pyroptosis and the secretion of cytokines (IL-1β and IL-18) should be
considered together as a potential inammatory mechanism in the
analysis of inammatory diseases. In the last decade, essential ndings
have revealed that gasdermin D (GSDMD) plays a mediating role in
pyroptosis. GSDMD features an amino-terminal cell death domain
(GSDMD
Nterm
), a central short linker region, and a carboxy-terminal
autoinhibition domain. GSDMD is released from caspase-1 cleavage to
escape intramolecular inhibition by removal of its carboxyl terminus(Shi
et al., 2015). GSDMD
Nterm
can oligomerize phosphatidylserine in the
inner leaet of the cell membrane and insert into the plasma membrane,
forming a 10–14 nm pore containing 16 symmetrical protomers, thus
killing cells from within(Ding et al., 2016). Additionally, GSDMD
Nterm
exerts bactericidal activity when bound to cardiolipin in outer and inner
bacterial membranes. The exact mechanism of this direct bactericidal
activity in the infection process has not yet been investigated. Activated
NLRP3 triggers cardiolipin phenomena in the inner and outer mito-
chondrial membranes. However, it is unclear whether GSDMD
Nterm
can
migrate into mitochondria by binding to mitochondrial cardiolipin.
Another pathway of GSDMD-mediated pyroptosis is through uncon-
ventional secretion of IL-1β and IL-18 release(Lieberman et al., 2019).
Pyroptosis plays a vital role in the secretion of IL-1
α
in the
calmodulin-processed form, although the process does not determine its
biological activity. The ndings described above reveal that GSDMD is
induced biochemically to undergo pyroptosis downstream of inam-
masome activation. Additionally, due to the critical role of caspase -1 in
IL-1β processing and pyroptosis, caspase -8 functions in the induction of
IL-1β and IL-18 maturation and cell death in unregulated pathways
(Antonopoulos et al., 2015). However, some studies have conrmed
caspase-8-mediated maturation of pro-IL-1β and pro-IL-18, which can
occur through NLRP3-independent and NLRP3-dependent pathways.
Together, these studies suggest that pyroptosis exerts a unique biological
effect that promotes inammation and inammasomes in the body.
2.4. LncRNAs and NLRP3 mRNA share similar biogenesis pathways
Similar to histone markers of NLRP3 mRNA, the lncRNA transcrip-
tion is performed by NAPII. Most of its structural changes include
capping at the 3’ ends and 5’ ends with 7’-methylguanosine, poly-
adenylation, and splicing(Derrien et al., 2012; Hon et al., 2017). Studies
have shown that Nonpolyadenylated lncRNAs, enhancer transcription,
and enhancer RNA may play regulatory roles during transcription, and
are not simply transcriptional noise(Natoli and Andrau, 2012). These
mechanisms are achieved by cleavage of ribonuclease P to generate
mature 3′ends, forming snoRNA–protein complexes, or capping circular
structures at their ends(Memczak et al., 2013; Yang Zhang et al., 2014).
The important difference between lncRNAs and mRNAs is that lncRNAs
are poorly conserved due to their lack of long ORFs and low
protein-coding potential (Derrien et al., 2012). However, interestingly,
Ruiz-Orera et al. found that lncRNAs show very similar characteristics
and sequence constraints to functional coding genes and may play an
active role in de novo protein evolution(Ruiz-Orera et al., 2014).
3. The regulatory relationship between lncRNAs and NLRP3
inammasomes
The central rule of molecular biology is the transcription of genetic
information from DNA to RNA and its translation into proteins. LncRNAs
have been found to function in inammation and immune-related cells,
such as T lymphocytes, B lymphocytes, and dendritic cells (DCS)(Geng
and Tan, 2016). LncRNAs participate in all cell function stages,
including cell differentiation, development, metabolism, and immunity
(Wu et al., 2015a). Numerous high-quality research data sets have
indicated that lncRNAs are engaged in various pathophysiological pro-
cesses, such as pain, tumours, ageing, neurodegenerative diseases, and
cardiovascular diseases via NLRP3 inammasomes(Guo et al., 2019; Xu
et al., 2018; Zhang et al., 2019c). Proteins related to the pyroptosis
signalling pathway are activated via a direct or indirect mechanism,
interact with pathogens, and regulate body immune responses(Bordon,
2019; Haque et al., 2020).
3.1. lncRNAs regulate the expression of the NLRP3 inammasome
through the ceRNA mechanism
Research has increasingly focused on the complex interaction be-
tween NLRP3 and various RNA species, including diverse noncoding
RNA (miRNAs, circular RNAs, and lncRNAs) and protein-coding mRNAs
(Hadjicharalambous and Lindsay, 2019). LncRNAs can compete with
NLRP3 to bind miRNA sponges to regulate the expression of target
genes. The NLRP3 inammasome is a miRNA target gene in various
diseases(Rituparno et al., 2014; Tay et al., 2014)(Fig. 3A). The ceRNA
mechanism allows lncRNA transcripts and NLRP3 to regulate and
communicate to affect mRNA expression by competing for natural
microRNA sponges, which have no protein-coding ability but regulates
NLRP3 mRNA expression through posttranscriptional regulation
degradation(Jiang et al., 2017; Wang et al., 2019a). The discovery of
this novel RNA crosstalk interaction mechanism will help gain signi-
cant insight into the lncRNA regulatory mechanism and impact human
diseases occurrence and development. It has been reported that
miR-135a reversed lncRNA DANCR regulation in the entire process of
promoting pancreatic cancer cells, which was attained by degrading the
downstream protein of NLRP3 in the cytoplasm(Y. Tang et al., 2019). In
ischaemia-reperfusion-injured hearts, lncRNA MALAT1 sponges
miR-133 to increase transcriptional expression of NLRP3 inammasome
(Yu et al., 2018). Furthermore, MALAT1 also competitively binds
miR-22 to affect NLRP3 expression in high glucose-induced human
endothelial cell pyroptosis(Song et al., 2019a). In those patients with
laryngeal squamous cell carcinoma (LSCC), lncRNA RGMB-AS1 could
make it competitive for molecular sponge miR-22 to attenuate NLRP3
transcription expression, and its reduction can suppress LSCC progres-
sion. Therefore, lncRNA RGMB-AS1 may become a new focus in the
diagnosis, treatment, and prognosis of LSCC because of its progress
through the ceRNA mechanism(Xu and Xi, 2019). LncRNA 00339 can
regulate the miR-22-3p/NLRP3 axis to promote renal tubular epithelial
cell pyrocytosis. Mechanistically, LINC00339 upregulates NLRP3
expression by sponging miR-22-3p, which acts as a competitive endog-
enous RNA(Song et al., 2019b). Zhang et al. have conrmed that lncRNA
NEAT1 was able to compete for binding to miR-3076-3p as a molecular
decoy of the NLRP3 inammasome by ceRNA. At the same time, Neat1
was found not only to bind to pro-caspase-1 but also facilitate the as-
sembly of NLRP3, NLRC4, and AIM2 inammasomes in mouse macro-
phages; Neat1 also was able to induce the maturation of IL-1β and cell
pyroptosis by activating caspase-1; thus a series of effects promoted the
expression of tolerogenic phenotype in DCs(Song et al., 2019b). In
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Parkinson’s disease, Long noncoding RNA SNHG1 contributes to neu-
roinammation by modulating the lncRNA SNHG1/miR-7/NLRP3
pathway(Cao et al., 2018). Certain drugs, like melatonin, can affect
the expression of lncRNA MEG3, leading to inhibition of endothelial cell
pyroptosis via regulation of the miR-223/NLRP3 signalling axis(Zhang
et al., 2018). Experimental evidence has conrmed that the lncRNAs
described above play an integral role in the regulation of gene expres-
sion of both competitions for miRNAs, small non-coding regulators, and
mRNAs(Salmena et al., 2011). Two new noncoding RNA participants,
lncRNAs, and miRNAs further increase RNA interactions through the
ceRNA mechanism(Ergun and Oztuzcu, 2015). Related literature has
analysed and veried the mechanism of ceRNA interaction through
bioinformatics and experimental methods, and this indicates that the
role of ceRNA is one of the transcriptional regulatory functions of
lncRNAs, which is even a different or complementary mechanism from
traditional protein-coding function(Tay et al., 2014; Yang et al., 2016).
3.2. LncRNAs regulate the expression of NLRP3 via the NF-κB/NLRP3
inammasome pathway
There are two studies about lncRNAs that can regulate the activation
of the NLRP3 inammasome by interacting with NF-κB, which is a
crucial participant in all of the inammatory phases in diabetic ne-
phropathy (DN) and inammatory diseases(Samra et al., 2016; Yang
et al., 2014). These results suggest that the lncRNA/NF-κB/NLRP3
inammasome signalling pathway may be a novel functional mecha-
nism in many diseases (Fig. 3B). LncRNA Gm4419 upregulates proin-
ammatory cytokines via the lncRNA/NF-KB/NLRP3 central
inammatory axis in mesangial cells (MCs) of DN(Yi et al., 2017). In the
present study about the bovine mammary epithelial cells and the in-
ammatory response, the NF-κB pathway was activated to mediate
inammation by enhancing the expression of XIST, which was part of a
negative feedback loop in the regulation of the NF-κB/NLRP3 pathway
(Ma et al., 2019). In addition, XIST inhibits NF-κB phosphorylation and
NLRP3 inammatory production through a pathway by inhibiting E. coli
or S. aureus-induced activity(Ma et al., 2019). In the latest article, Zhang
et al. found that lncRNA-far1 was involved in NLRP3
inammasome-mediated pyroptosis and BDL- and CCl4-induced proin-
ammatory of M1 macrophages(Zhang et al., 2020b). Furthermore, the
results of animal experiments have revealed that silencing lnc-far1 also
signicantly inhibited NLRP3 inammasome-mediated pyroptosis acti-
vation of macrophages(Zhang et al., 2020b).
3.3. LncRNAs regulate the expression of NLRP3 by direct interaction of
lncRNAs and proteins
LncRNAs regulate the expression of NLRP3 by inhibiting the encoded
TXNIP, constituting a newly discovered regulatory mechanism. TXNIP is
a crucial intermediary mediator linking the regulation of lncRNA and
NLRP3 inammasome activation in oxidative- and endoplasmic reticu-
lum (ER) stress-related disease(Anthony and Wek, 2012)(Fig. 3C).
LncRNA Gm15441 expression can suppress its antisense transcript to
modulate the expression of TXNIP. TXNIP can be encoded by upregu-
lating lncRNA Gm15441, which results in a downregulated expression of
TXNIP activating the NLRP3 inammasome followed by cleavage of
caspase-1, in turn, promoting pro-IL-1β to induce the maturation of IL-1β
(Brocker et al., 2019). The study shows that the upregulated lncRNA
gene Gm15441 can directly bind the promoter of nuclear
receptor-peroxisome proliferator-activated receptor alpha (PPARA) to
activate its ligand. Thus, we understand this regulatory mechanism by
which liver PPARA directly up-regulates lncRNA Gm15441 expression
by inhibiting Txnip encoding, in turn, repressing the activation of the
NLRP3 inammasome during metabolic stress(Brocker et al., 2019). A
recent study result shows that lncRNA Gm14205 regulate the expression
of NLRP3 by inhibiting the encoded OXTR by direct interaction of
lncRNA and protein(Zhu and Tang, 2020). The results of these studies
demonstrate an innovative indirect, interactive mechanism between
lncRNAs and NLRP3, which supports the benecial effects of intestinal
fasting during inammation to reduce food irritation.
3.4. LncRNAs promote the assembly of the NLRP3 inammasome
LncRNAs function as regulators in promoting various inammatory
factors in the cytoplasm under certain stimulatory conditions(Fig. 3D).
NEAT1 also plays an essential role in regulating the expression of che-
mokines and inammatory factors (including IL-6 and CXCL10) by
indirectly regulating NLRP3 activation (Zhang et al., 2016). We note
that many stimuli affect the expression of the lncRNA Neat1 and activate
Fig. 3. Regulatory mechanisms between long
non-coding RNAs (lncRNAs) and NLRP3 in the
cytoplasm and nucleus: (A) as a molecular
sponge, inhibiting microRNA (miRNA) function
by competing for binding with them; (B) tar-
geting proteins to exert positive or negative
activity by forming new molecular complexes or
altering their subcellular location; (C) as a
decoy to structural proteins affecting their
binding DNA sites, such as with remodelling
transcription factors inuencing chromatin
structure; (D) as molecular scaffolds, assem-
bling different proteins and forming new pro-
tein complexes, which regulate gene
transcription; (E) binding messenger RNAs
(mRNAs) and promoting their degradation to
alter their effects.
D. Luo et al.

Molecular Immunology 131 (2021) 191–200
196
inammasomes. NLRP3 inammasome assembly and activation can be
induced by many stimuli, including various viruses, extracellular ATP,
by-products of oxygen metabolism (e.g., ROS), potassium efux, frus-
trated phagocytosis, and phagolysosome disruption. (Martinon, 2010).
One current study demonstrated that Neat1 promoted the assembly of
NLRC4, AIM2, and especially NLRP3 inammasomes, thereby activating
inammatory factor expression(Zhang et al., 2019b). Neat1 also en-
hances mature caspase-1 tetramer structural stability and increases its
protease activity by binding target sites. Neat1 likely performs a func-
tion to facilitate recruitment, assembly, stabilization, caspase-1 matu-
ration, and secretion by assembling a largely proteinaceous signalling
platform in activated macrophages(Zhang et al., 2019b), most likely
previously unanticipated. Furthermore, a joint priming event leads to
inammasome assembly, such as by TLRs, which promote the activation
and expression of NLRP3 and pro-IL-1β(Schroder and Tschopp, 2010;
Tang et al., 2012). The interaction between lncRNA Neat1 and NLRP3
inammasomes establishes an indirect regulatory mechanism of size-
able multimeric protein complexes in the cytoplasm.
3.5. LncRNAs decrease NLRP3 expression by inhibiting its promoter
activity
The NLRP3 inammasome is a complex protein that includes a
leucine-rich repeat-containing protein family of intracellular sensors
and a nucleotide-binding domain that can activate the promoter region
via main domain changes(Cassel et al., 2009). Recent research data have
afrmed that the NLRP3 inammasome plays a critical role in the
metastasis and invasion of multiple cancers, such as breast cancer,
melanoma, hepatocellular carcinoma, etc., (Ahmad et al., 2013; Karki
et al., 2017). The long noncoding RNA XLOC_000647 can inhibit NLRP3
inammasome activation by downregulating NLRP3 expression in
pancreatic cancer, which can block pancreatic cancer cell proliferation,
metastasis, epithelial-mesenchymal transition-induced cell invasion,
and EMT(Hu et al., 2018). The up-regulation of lncRNA XLOC_000647
expression can reduce the luciferase activity of the NLRP3 promoter
region to achieve function in vitro. Therefore, the cited study found that
lncRNA XLOC_000647 may inhibit the entire progression of pancreatic
cancer (PC) by negatively regulating the activation of NLRP3. These
results expand our understanding of the mechanisms underlying the
roles of lncRNAs and the NLRP3 inammasome and provide insights
into the clinical diagnosis and treatment of various tumours. This study
provides a new indirect molecular regulatory mechanism in the inter-
action between lncRNAs and the NLRP3 inammasome (Fig. 3E).
4. LncRNAs and NLRP3 inammasomes in various diseases
4.1. LncRNAs and NLRP3 in inammatory diseases
The biological and clinical roles of lncRNAs and the NLRP3 inam-
masome have recently been studied extensively in the inammatory
response and inammatory cascade reaction(Haque et al., 2020; He
et al., 2019). Zhang et al. speculated that the lncRNA Neat1 regulated
activation of inammasomes by assembling NLRP3, NLRC4, and AIM2
components and promoted IL-1β induced pyroptosis by stabilizing the
mature caspase-1 in mouse macrophages(Zhang et al., 2019b). In the
common pathways of various inammatory activation signals, Neat1
usually participates in NLRP3 inammatory activation by changing its
subcellular position to function after being released from the speck and
transferred to the cytoplasm. These results indicate that Neat1 acts as a
common mediator of inammasome stimuli via the direct regulatory
mechanism between Neat1 and the NLRP3 inammasome. In another
study, results showed that NEAT1 knockdown generates a tolerogenic
phenotype in dendritic cells by inhibiting NLRP3 activity(Zhang et al.,
2019a). Mechanistically, RNA sequence analysis showed that silenced
NEAT1 mainly targets miR-3076-3p and affects its expression in DCs.
NEAT1 knockdown can also induce DCs to develop immune tolerance in
organ transplantation models and autoimmune disorder myocarditis.
Silencing of lncRNA XIST can upregulate proinammatory cytokines by
inducing the activation of E. coli or S. aureus-induced In bovine mam-
mary epithelial cell inammatory responses(Ma et al., 2019).
Additionally, XIST knockdown inhibited E. coli or S.aureus-induced
NF-κB phosphorylation and cell proliferation, suppressed cell viability,
and eventually `guided cell apoptosis upon activation of the NLRP3
inammasome. We know that the long non-coding RNA MALAT1 is
closely related to apoptosis. In the pyroptosis of high glucose-induced
endothelial cells, pyroptosis, lncRNA MALAT1 plays a role in the pro-
cess by partially promoting the expression and activation of NLRP3 by
competitively binding miR-22(Song et al., 2019a). These results reveal
that the interaction between lncRNAs and NLRP3 may be widely
involved in the progression of these inammatory diseases.
4.2. lncRNAs and NLRP3 in gastroesophageal cancer
A group of lncRNAs has been found to be associated with cancer by
various means(Arun et al., 2018; Choudhari et al., 2020; de Oliveira
et al., 2019; Spizzo et al., 2012). LncRNAs and NLRP3 are increasingly
involved in tumour formation, metabolism, treatment, targets, and
related models. Hu et al. found that overexpression of XLOC_000647
inuences clinical tumour stage, size, lymph node metastasis, and
overall survival(H. Hu et al., 2018). They also observed that the
expression level of XLOC_000647 was negatively associated with NLRP3
activity in vivo and in vitro. The results show that XLOC_000647
dramatically reduces NLRP3 promoter movement, decreasing cancer
proliferation, invasion, and EMT in vitro. Tang et al. also found that the
lncRNA DANCR could promote cancer cell proliferation, aggression, and
EMT by regulating the miR-135a/NLRP3 axis in pancreatic cancer cells
in animal experiments(Tang et al., 2019). LncRNAs may be a new target
for diagnosis and treatment. In gastric cancer (GC), some investigators
have revealed that lncRNA ADAMTS9-AS2 mediates GC cell pyroptosis
via regulation of the miR-223-3p/NLRP3 axis by acting as a tumour
suppressor and enhancing cisplatin sensitivity. The interaction between
lncRNA RGMB-AS1 and NLRP3 plays specic functional roles in LSCC.
In addition, the high expression of RGMB-AS1 is closely related to
advanced clinicopathological characteristics and poor prognostic out-
comes(Xu and Xi, 2019). The silencing of lncRNA RGMB-AS1 can sponge
miR-22 and upregulate NLRP3 inammasome expression levels, which
inhibits the proliferation and invasion of LSCC cells in vitro and sup-
presses tumour growth in vivo(Xu and Xi, 2019). Taken together,
revealing the mechanism of interaction of lncRNA and NLRP3 in
digestive cancer may bring new prospects for treating these diseases.
4.3. LncRNAs and NLRP3 in nephropathy
In recent years, the roles of lncRNAs have received increasing
attention. The typical clinical manifestations of uric acid nephropathy
(UAN) are hyperuric acid, oedema, oliguria, proteinuria, and hyper-
tension. UAN is a type of urate crystal deposition caused by purine
metabolism disorders and eventually leads to inammation activation
and induce immune-changing diseases(Hou et al., 2014). The long-chain
noncoding RNA ANRIL is involved in the NF-κB-mediated inammatory
response and its high expression has been shown in the serum of UAN
patients and kidney tissues of an adenine-induced rat model(Hu et al.,
2019). Hu et al. reported that ANRIL can act as a competitive sponge for
particular miRNA to reduce NLRP3 degradation and activate it to exert a
pathogenic effect via the miR-122-5p/BRCC3 axis in UAN patients(Hu
et al., 2019). In diabetic nephropathy, Li et al. revealed that MALAT1
promotes renal tubular epithelial cell apoptosis through the same ceRNA
mechanism, combined with the targeting of ELAVL1 by miR-23c to
regulate expression of its downstream protein NLRP3(Li et al., 2017). Yi
et al. also found that silencing lincRNA-Gm4419 could signicantly
downregulate the expression of NLRP3 inammasome-mediated
inammation via the NF-κB/NLRP3 axis in diabetic nephropathy(Yi
D. Luo et al.

Molecular Immunology 131 (2021) 191–200
197
et al., 2017). The same regulatory mechanism of interaction between
lncRNA and NLRP3 inammation was found in calcium oxalate–induced
kidney stones by Song et al. Their research conclusion revealed that
LINC00339 could cause renal tubular epithelial pyroptosis via the
miR-22-3p/NLRP3 ceRNA (Song et al., 2019b). Therefore we speculate
that inammation resulting from the interaction of lncRNAs and NLRP3
plays various important roles in diabetic nephropathy. A better under-
standing of this mechanism of regulating diabetic nephropathy patho-
genesis by long noncoding RNAs may facilitate the development of a
potential therapeutic strategy and criteria for diagnosis.
4.4. LncRNAs and NLRP3 in neuroinammation
Neuroinammation may be closely related to inammatory re-
actions, neuro infections, neurodegenerative changes, and other related
diseases. The specic regulatory mechanism of noncoding RNAs is not
yet evident in the whole process. In neuroimmunology, recent research
evidence has found that lncRNAs could be involved in neuroimmune
functions, such as regulation of the mass production of neuro-
inammatory mediators and DNA-protein and RNA-RNA interactions to
control cell proliferation, invasion, differentiation, migration, and sur-
vival(Heward and Lindsay, 2014). Recent studies have conrmed that
changes in lncRNA expression act as an essential regulatory participant
not only in the adaptive process but also in the adaptive immune
response; lincRNA-Cox2, which is also known as Ptgs2, is located at the
51 kb locus near the functional gene Cox2, and its expression is upre-
gulated through Tlr4 stimulation-induced lincRNA-Cox2 in bone
marrow-derived dendritic cells(Guttman et al., 2009). Xue et al. found
that lincRNA-Cox2 was able to target NF-κB p65 to modulate NLRP3 and
ASC activity by enhancing its nuclear translocation and transcription
(Xue et al., 2019). The silencing of lincRNA-Cox2 can downregulate
NLRP3 inammasome expression by disrupting NLRP3-mediated ASC
complex formation under LPS-induced stimuli. Inhibition of NLRP3
inammasome activity leads to caspase-1 inactivation, reducing the
release of TIR domain-containing adapter-inducing interferon-β (TRIF);
therefore, the nal product derepresses TRIF-mediated ATG5-dependent
autophagy. In the progression of Parkinson’s disease (PD), the lncRNA
Snhg1 can sponge endogenous RNA miR-7 to regulate activation of the
NLRP3 inammasome(Cao et al., 2018). These research results provide
a better understanding of the interactive regulatory mechanism between
lncRNAs and the NLRP3 inammasome, which may be a potential op-
portunity for prophylaxis, diagnosis, and therapeutic intervention in
neuroinammation-related diseases.
4.5. LncRNAs and NLRP3 in liver diseases
In a recent study, lncRNAs and NLRP3 were involved in the devel-
opment and evolution of hepatic brosis, closely associated with
pyroptosis, the nal programmed inammatory cell death process.
Zhang et al. found that M1 macrophage activation and pyroptosis could
be regulated by silencing lnc-Lfar1 through excessive pyroptosis of CCl4-
and BDL- induced proinammatory factors(Zhang et al., 2020b).
Mechanistically, lnc-far1 regulated the activation of LPS- and
IFN-γ-induced proinammatory factors in macrophages via the
NF-ĸB/NLRP3 axis(Zhang et al., 2020b). The lncRNA-Gm15441 can
prompt elevated mature caspase-1 and IL-1β cleavage due to its sus-
ceptibility to NLRP3 inammasome activation under metabolic and
external inammatory stimuli(Brocker et al., 2019). These experimental
ndings provide new evidence for interpreting this novel mechanism by
which how they attenuate hepatic inammasome activation in the
progression of hepatic brosis and hepatic inammasome diseases.
4.6. LncRNAs and NLRP3 in cardiovascular diseases
In cardiovascular diseases of the circulatory system, high-throughput
sequencing has detected and characterized abnormal lncRNA expression
under pathophysiological conditions(Zhang et al., 2019c,d). The inter-
action between the NLRP3 inammasome and lncRNAs is involved in
structural heart disease and coronary heart disease(Uchida and Dimm-
eler, 2015). Atorvastatin can inhibit pyroptosis, which is one kind of
programmed cell death by changing biomarker (such as NLRP3,
caspase-1, ASC, IL-1 β, IL-18, etc.) expression levels of the NLRP3
inammasome pathway in atherosclerosis (AS) (Wu et al., 2020). The
precise mechanism is that the upregulation of the lncRNA NEXN-AS1
expression levels under pathological conditions directly regulates its
target gene NEXN in HVECs(Wu et al., 2020). In another experiment on
aortic endothelium of melatonin-treated animals with AS, the expression
of pyroptosis-related genes was signicantly reduced after melatonin
treatment; these inammatory factors included NF-κB/GSDMD, NLRP3,
ASC, Caspase-1, IL-1β, and IL-18 in the whole pathway(Zhang et al.,
2018). Human aortic endothelial cell (HAECs) pyroptosis can be
enhanced by activation of the NLRP3 inammasome through
lncRNA-MEG3/miR-223/NLRP3 ceRNA network(Yong Zhang et al.,
2018). In this process, lncRNA-MEG3 functions as an endogenous
sponge sequence complementing miR-223 and inhibits its expression
(Zhang et al., 2018). In the process of cardiac broblast apoptosis and
cardiac brosis disease, the main regulatory factor, lncRNA-GAS5, was
found to play an important role. Further research results revealed that
DNMT1 of lncRNA GAS5 activated the NLRP3 inammasome in the
progression of cardiac broblast pyroptosis(She et al., 2020). These are
the regulatory mechanisms of cardiovascular tissue apoptosis under LPS
stimulation, and provide a new therapeutic target for cardiovascular
diseases.
4.7. LncRNAs and NLRP3 in retinal ischaemia/reperfusion
Wang et al. reported that lncRNAs could be involved in ischaemic/
reperfusion by their transcriptional control of inammatory responses
(Wan et al., 2019). There are core causes of visual impairment or
blindness by I/R injury based on diverse retinal diseases, such as
infection, glaucoma, central retinal artery stenosis or obstruction, and
diabetic retinopathy(Paul Kamdem et al., 2016). Abnormal expression
of various immune cells and inammatory cytokines is closely related to
all I/R injuries(Yang et al., 2015). Some investigators have found that
the lncRNA H19/miR-21/PDCD4 ceRNA net forms a ceRNA mechanism
to change PDCD4 expression to regulate cytokine overproduction,
neuronal lesions, and I/R-induced sterile inammation(Wan et al.,
2019). Additionally, the lncRNA H19 is also involved in microglial
pyroptosis, neuronal death, and mitochondrial dysfunction through this
ceRNET. This intermolecular regulation mode enriched the regulatory
mechanism between lncRNAs and NLRP3 and facilitated prophylaxis
and I/R injury treatment.
4.8. LncRNAs and NLRP3 in intervertebral disk degeneration
In intervertebral disc degeneration, some studies have veried that
the change in lncRNA expression level signicantly increased in the
course of disease(Chen et al., 2017; Li et al., 2018; Mi et al., 2018). In a
current study, overexpressed LINC00969 massively bound to
miR-335-3p, which led to aberrant downregulation of the expression of
miR-335-3p in the nucleus pulposus (NP) tissues and cells of interver-
tebral disk degeneration patients(Yu et al., 2019). LINC00969 also en-
hances NP cell apoptosis in tissues by acting as a molecular bridge,
competing for miR-335-3p to modulate TXNIP expression and NLRP3
inammasome activation in vitro(Yu et al., 2019). These results provide
a reference mechanism on the mutual interaction between LINC00969
and NLRP3 to regulate the expression of the NLRP3 inammasome and
participate in the treatment and diagnosis of intervertebral disk
degeneration.
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Molecular Immunology 131 (2021) 191–200
198
5. Conclusion
In summary, the interaction of the NLRP3 inammasome and
lncRNAs has been most intensively investigated in various diseases,
including cancer, pyroptosis, Alzheimer’s disease, neuroinammation,
cardiovascular diseases, I/R injury, and inammatory diseases. There is
increasing evidence that lncRNAs mainly regulate the NLRP3 inam-
masome associated with pathophysiological processes pre- and post-
transcription. We still know very little about their precise regulatory
mechanisms during the complex pathophysiological evolution of dis-
eases, such as phagocytosis, adhesion, chemotaxis, exocytosis, and an-
tigen presentation. Furthermore, we also rarely know-how domains
accurately activate the NLRP3 inammasome: by protein interactions or
RNA interactions. These ndings will help us identify the functional
interaction between lncRNAs and NLRP3 according to sequence and
structure. Finally, with increasing discoveries related to lncRNAs and
disease development, and the mechanism of action being investigated,
lncRNA and NLRP3 interactions have new drug targets for allergies,
autoimmune diseases, cancer, pain, chronic inammation, and in-
fections. These research data provide insights into the mutual regulation
of lncRNAs and NLRP3 inammatory bodies and open up potential new
avenues to treat many diseases.
Author contribution statement
Author: Deqiang Luo Contribution: 1. Design research direction 2.
Write papers. Author: Fen Liu Contribution: 1. Collect references and
analysis 2. Review and revise the papers.
Author：Wenqiang Tao Contribution：Review and revise the
papers.
Author：Rui Xiao Contribution：Review and revise the papers
Author：Jianguo Zhang Contribution：Review and edit the article.
Author：Qiang Shao Contribution：Review and revise the papers.
Author：Wei Dai Contribution：Review and revise the papers.
Author: Keqian Qian Contribution: 1. Review and revise the papers,
2.guidance article writing.
Funding
The study accepts the National Natural Science Foundation of China
(81560306 and 81460292) and Graduate Student Innovation Special
Fund Project of Jiangxi Province (YC2020-B033).
Ethical approval and consent to participate
This article does not involve any studies with patients or animals
performed by any of the authors.
Declaration of Competing Interest
There is no conict of interest in this study. All authors declare that
they have no conict of interest.
Acknowledgments
We are grateful to the personnel of all the hospitals who participated
in this article for their support during design and revision. This work was
funded by a grant from The First Afliated Hospital of Nanchang
University.
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