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Gynecological Endocrinology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/igye20
Pyroptosis and inflammasomes in obstetrical and
gynecological diseases
Shu-Yue Yu & Xue-Lian Li
To cite this article: Shu-Yue Yu & Xue-Lian Li (2021): Pyroptosis and inflammasomes in
obstetrical and gynecological diseases, Gynecological Endocrinology
To link to this article: https://doi.org/10.1080/09513590.2021.1871893
Published online: 12 Jan 2021.
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REVIEW
Pyroptosis and inflammasomes in obstetrical and gynecological diseases
Shu-Yue Yu
a,b
and Xue-Lian Li
a,b
a
Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, P.R. China;
b
Shanghai Key Laboratory of Female
Reproductive Endocrine-Related Diseases, Fudan University,, Shanghai, P.R. China
ABSTRACT
Pyroptosis, an inflammatory form of programmed cell death, takes an essential part in a wide variety of
physiological activities, for instance, implantation, placentation and the body’s defense against infection.
However, once excessively activated, pyroptosis mediated by the activation of inflammasomes can be
highly pathological. It can cause inflammatory and autoimmune diseases including a variety of obstetrical
and gynecological diseases, such as endometriosis, gestational diabetes mellitus, insulin resistance in poly-
cystic ovary syndrome, and multiple obstetric complications including preeclampsia. Although the role of
pyroptosis in the pathogenesis of the above mentioned diseases has not been fully elucidated, we try to
tap its therapeutic potential by targeting pyroptosis signaling and inflammasome formation. Pyroptosis
and inflammasomes are confirmed to be involved in endometriosis and gynecological malignant tumors,
therefore, medical approachs inducing pyroptosis of the ectopic endometrium and tumor cells can be
feasible treatments for endometriosis and gynecological cancers. On the maternal-fetal interface, although
a certain level of the innate immune response activation is required for a successful implantation and pla-
centation, maternal and fetal injury may occur once the inflammasomes are over-activated. Besides, since
gestational diabetes mellitus and insulin resistance in polycystic ovary syndrome share common patho-
genesis with metabolic diseases, this domain research sheds light on future study of some obstetrical and
gynecological diseases.
ARTICLE HISTORY
Received 15 September 2020
Revised 5 December 2020
Accepted 2 January 2021
Published online 12 January
2021
KEYWORDS
Pyroptosis; inflammasomes;
endometriosis; gestational
diabetes mellitus; polycystic
ovarian syndrome
Introduction
Pyroptosis, an inflammatory form of programmed cell death [1],
also known as Gasdermin-dependent necrosis, is an essential
part of the innate immune response. Pyroptosis was initially
identified in the macrophage in 1992 [2] to describe the inflam-
matory nature of caspase-1-dependent lysis after infection with
Shigella flexneri [3]. The name of pyroptosis was coined in 2001
[1] while inflammasomes were described as caspase-1 activating
multiprotein complexes one year later for the first time [4].
Compared with its well-known counterparts, such as apoptosis,
autophagy and anoikis [5], pyroptosis is a much faster process. It
relies on the activation of specific inflammatory caspases, includ-
ing caspase-1, human caspase-4 and caspase-5, as well as murine
caspase-11 [6].
Morphologically, nuclei of the cells remain intact [7] in the
process of pyroptosis. Without the nucleus disolving, pyroptosis
manifests as cell swelling, plasma membrane lysis, chromatin
fragmentation [8] and is accompanied by the release of a large
quantity of several intracellular pro-inflammatory cytokines such
as interleukin-1b(IL-1b) and interleukin-18 (IL-18). These cyto-
kines trigger inflammatory reactions when released to extracellu-
lar domain [9]. Therefore, they usually causes damage to the
body [10].
Molecularly, pyroptosis can be triggered by the activation of
pattern-recognition receptors and the accompanying inflamma-
tory responses [11]. In general, pattern-recognition receptors can
be classified into two categories. One locates on the plasma and
endosomal membranes and recognizes both damage-associated
molecular patterns and pathogen-associated molecular patterns
in the extracellular environment. The other recognizes damage-
associated molecular patterns in intracellular environment. Toll-
like receptors are the typical representative of the former while
nucleotide-binding oligomerization domain(NOD)-like receptors
(NLRs) stand for the later [12]. Biological pathogens such as bac-
terium and viruses, together with non-biological signals, includ-
ing endogenous stimuli and ischemic necrosis products, serve as
stimuli for intracellular pattern-recognition receptors and activate
inflammatory caspases by forming specific inflamma-
somes [13,14].
Inflammasomes are cytosolic multiprotein complexes, identi-
fied as a series of NLRs, including NOD1, NOD2 and the NOD-
like receptor protein (NLRP) [15]. They respond to a variety of
endogenous (i.e. damage-associated molecular pattern) and
exogenous (i.e. damage-associated molecular pattern) stimuli
[16]. Once activated, capsases cleave the connection between the
amino and carboxyl terminal of Gasdermin D. Thus, it breaks
the self-inhibition of its two terminals and cleave it into the N-
terminal domain (Gasdermin D-NT) and the C-terminal domain
(Gasdermin D-CT) [17]. The generated Gasdermin D-NT [18]
acts on the the phopholipid layer of cell membrane. It results in
swelling and osmotic lysis, which leads to a chain of reactions
including the pore formation of cytomembrane, cell rupture,
release of cytosolic protein, and eventually causing cell pyroptosis
[19]. As mentioned above, the pore formation in the plasma
membrane of these cells is dependent on the activation of cas-
pase-1 [20], leading to the permeability of plasma membrane.
CONTACT Xue-Lian Li xllifc@fudan.edu.cn Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai
200011, P.R. China.
ß2021 Informa UK Limited, trading as Taylor & Francis Group
GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2021.1871893
Emerging evidence indicates that inflammasomes can be con-
sidered as protective response to harmful stimuli to preserve or
restore the integrity of the body [21]. Cell pyroptosis plays a cru-
cial role in regulating the function of immune cells during mul-
tiple extraneous infections and responding to endogenous risk
signals [22]. However, once over-activated continuously, pyrop-
tosis can lead to immune dysregulation [23] and excessive
inflammation response. These reactions will result in a number
of inflammatory and immune diseases [24], including metabolic
disorders, atherosclerosis and other vital organ damage, or even
tumorigenesis.
In recent years, the most highlighted inflammasome is the
NLRP3 inflammasome, which is associated with the onset and
progression of quite a few autoinflammatory and autoimmune
diseases. NLRP3 has become a fresh promising therapeutic target
[25] since it plays a role in systemic lupus erythematosus [26]
and several metabolic disorders such as diabetes mellitus [27,28],
inflammatory bowel disease such as Crohn’s disease [29], athero-
sclerosis [30] and other chronic cardiovascular diseases [31].
NLRP3 is also associated with a wide variety of tumorigenesis
[32]. Therefore, it can be monitored to evaluate chemotherapy
response and prognosis of cancer patients.
Many recent studies have come to the role of pyroptosis in
the pathogenesis of several gynecological and obstetrical diseases.
Hence, this review aims to provide a current overview of the
known regulatory mechanism of pyroptosis and inflammasomes
particularly in gynecological and obstetrical disorders as well as
in metabolic, inflammatory and immune diseases. Furthermore,
we will disscuss the therapeutic potential for the above-men-
tioned diseases through targeting pyroptosis signaling and
inflammasome formation.
Pyroptosis and inflammasomes in endometriosis
Endometriosis is a common gynecological disease causing dys-
menorrhea, menstrual disturbance and even infertility. It is also
correlated with myometrial invasion in human endometrial can-
cer tissue and a risk factor for a bunch of pelvic malignant
tumors including ovarian cancer [33]. The mechanism of endo-
metriosis remains controversial. Despite the fact that menstrual
blood reflux can be observed in approximately 90% of woman
during menstruation, only 10–15% woman actually suffer endo-
metriosis [34]. We assume that apart from the well-known
pathogenesis of endometriosis, namely the ectopic planting the-
ory and the celomic metaplasia theory [35], inflammatory patho-
genic mechanisms are likely to be involved in endometriosis as
well, among which inflammasome certainly plays an essen-
tial role.
Bullon et al. [36] have shown that endometriosis is related
with IL-1band inflammasomes. Except immune cells of the
myeloid lineage, inflammasomes are observed mainly in epithe-
lial cells from tissues with mucosal surfaces [37]. Although there
is yet no specific evidence, the most common ectopic endomet-
rium plants on the surface of the ovary, which is covered with
germinal epithelium. While expression of NLRP3 is just about
absent in endometrial tissues acquired from healthy women, the
majority of samples acquired from women with endometriosis
exhibited boosted expression of NLRP3 [38]. These evidences
may indicate a certain role of pyroptosis in the pathogenesis of
endometriosis.
The steroid receptor coactivator-1 isoform/estrogen receptor-
baxis has a crutial role in endometriosis progression. Dr. Cho
Y’s research team finds that serving as inhibitor of steroid
receptor coactivator, Bufalin is able to effectively increase steroid
receptor coactivator-1 isoform protein stability as well as hyper-
activate the steroid receptor coactivator-1 isoform transcriptional
activity in endometriotic lesions. Therefore, the drug disrupts the
functional axis of steroid receptor coactivator-1 isoform/estrogen
receptor-b. In the stromal cells of endometriotic lesions from
mice models with surgically induced endometriosis, Bufalin treat-
ment increases the levels of caspase-1 and the active form of IL-
1b. It induced pyroptosis and apoptosis in endometriotic lesions,
thus, reduced proliferation and eventually suppressed the growth
of endometriotic lesions significantly [39]. In this case, future
generations of steroid receptor coactivator-modulators could be
employed as an alternative medical approach for endometri-
osis treatment.
Women with endometriosis are generally at an enhanced risk
of developing adhesions even in the absence of surgery, and acti-
vation of inflammasomes may be critical to promote the devel-
opment of endometriosis-related adhesion situation of the pelvic
cavity. Therapeutically targeting inflammasomes may prevent
adhesions in patients with endometriosis [40].
These new clues regarding the pathogenic mechanisms involv-
ing inflammasomes and pyroptosis may be crucial in the future
development for the clinic treatment of endometriosis.
Pyroptosis and inflammasomes in
gynecological oncology
Pyroptosis and inflammasomes are considered to play a dual role
in multiple tumor pathogenesis [41]. On the one hand, the mul-
tiple inflammatory mediators released during pyroptosis are
bound up with the malignancies as well as their drug resistance
to chemotherapeutics [42]. Several studies have shown that
pyroptosis and inflammasomes take part in the occurrence and
development of gynecological malignant tumors. The Human
Protein Atlas suggests that human ovarian tumors express
NLRP3, caspase-1, IL-1band IL-18 [43]. Compared to normal
female, increased protein expression of caspase-1, IL-1b, and IL-
18 occurred in surface epithelium, tumor cells, and immune cells
from patients with ovarian cancer [44]. In 2018, Chang found
high expression levels of AIM2 and NLRP3 were significantly
correlated with low progression-free survival in patients with
ovarian cancer [45] Similarly, in the case of endometrial carcin-
oma, the expression of NLRP3, Gasdermin D, caspase-1 and IL-
1bwere also significantly higher in atypical hyperplasia and can-
cer tissues than in benign endometrial tissues [46]. Moreover,
studies suggest that the expression level of NLRP3, Gasdermin D
and caspase-1 in endometrial cancer may be related to patients’
survival rate [47]. From the above, we believe patients with ovar-
ian or endometrial cancer are under systemic inflammatory con-
ditions and have elevated oxidative stress. However, seen from
the opposite angle, the activation of pyroptosis as the inflamma-
tion-mediated cell death pathway may facilitate the elimination
of tumor cells. Thus, pyroptosis inhibits the malignant progres-
sion of tumors, which makes it a druggable target [48]. In fact,
some studies indicate that chemotherapy drugs and target ther-
apy drugs could trigger pyroptosis in various types of cancer,
and pyroptotic death can suppress the occurrence and develop-
ment of cancers. Pharmacological activation of pyroptosis elimi-
nates malignant tumor cells and has become one optional
treatment of cancers [49]. A recent study has revealed that a
functional food ingredient, nobiletin, represents a promising new
anti-ovarian cancer candidate. By decreasing mitochondrial
membrane potential and inducing reactive oxygen species
2 S.-Y. YU AND X.-L. LI
generation, it contributes to Gasdermin D-mediated pyroptosis
in ovarian cancer cells [50]. Likewise, the novel molecule 2-
(anaphthoyl)ethyltrimethylammonium iodide (a-NETA) treat-
ment dramatically decreased the size of epithelial ovarian cancer
tumors in mice in an in vivo experiment. It suggests that
a-NETA can be a potential antitumor molecule or lead com-
pound for ovarian cancer. a-NETA significantly increased the
expression of pyroptosis-associated molecules including caspase-4
and Gasdermin D in ovarian cancer cells. Besides, knockdown of
either caspase-4 or Gasdermin D in ovarian cancer cells strongly
interfered with the cell-killing activity of a-NETA, which also
indicated that a-NETA induces epithelial ovarian cancer cell
pyroptosis through the pyroptosis pathway [51].
With the gradual analysis of its mechanism, pyroptosis pro-
vides an inestimable new direction for the diagnosis and treat-
ment of cancer.
Pyroptosis and inflammasomes in maternal-
fetal interface
Inflammasome can be a double-edged sword when it comes to
the field of maternal-fetal interface. On the one hand, endomet-
rial remodeling during the early stage of implantation can be
construed as the death of endometrial cells. Therefore, a proper
innate immune response activation is required for successful
implantation and placentation [52]. On the other hand, inflam-
masomes emerge as critical innate sensors of the maternal
immune system that defense against pathogen infection. They
are involved in the pathogenesis of preeclampsia and other preg-
nancy syndromes associated with placental inflammation, and
may lead to both maternal and fetal injury [53].
Since the pore-forming function of Gasdermin D is consid-
ered as the key to pyroptosis, we can presume that the detection
of Gasdermin D represents in vivo evidence of pyroptosis.
Recent research shows a significantly increased Gasdermin D
level in the amniotic fluid and chorioamniotic membranes of
women who underwent spontaneous labor at term compared to
those without spontaneous labor [54]. This result provides evi-
dence for the participation of pyroptosis in the sterile inflamma-
tory process of term parturition.
In 2018, Dr. Suzuki investigated different cell-death pathways
in uterine tissue obtained from pregnant cows. Uterine tissues
were all collected on day 18 of pregnancy from the bovine uter-
ine. The results suggested that both the expression of apoptosis-
related genes (caspase-7, 8, and fas-associated protein with death
domain (FADD)) and pyroptosis-related genes (caspase-4, 11,
and NLRP3) were significantly higher in the pregnant subjects in
comparison to the non-pregnant ones. On the other hand, preg-
nancy did not seem to have an effect on autophagy-related genes.
Furthermore, Dr. Suzuki cultured bovine endometrial epithelial
cells in vitro with a type I interferon, interferon-tau stimulation.
interferon-tau is known as pregnancy recognition signaling mol-
ecule secreted from the bovine conceptus during their preim-
plantation period. He came up with some similar results,
showing that interferon-tau affected both the increase of apop-
tosis-related (caspase-8) and pyroptosis-related (caspase-11)
genes, while the autophagy-related gene expression was not
effected either [55].
Nevertheless, when infections such as Group B streptococci
occur either in utero or in newborn, streptococcal lipid toxin
induces membrane permeabilization which triggers K(þ) efflux,
and NLRP3 inflammasome is activated by the exogenous
pathogenic stimuli, leading to osmotic lysis of red blood cells or
pyroptosis in macrophages [56].
These researches confirmed the necessity of apoptosis and
pyroptosis in placental implantation in the early stage of a nor-
mal pregnancy. However, emerging studies have suggested that
once activated inappropriately, pyroptosis and inflammasomes
can also become a part of the pathogenesis of multiple obstertri-
cal diseases which may have an adverse impact on maternal and
fetal health and cause poor pregnancy outcome.
Preeclampsia is a vital link in pregnancy-induced hyperten-
sion, as well as a leading cause of maternal and fetal morbidity
and mortality. In preeclampsia, local hypoxia and ischemia cause
a disrupted regulatory mechanisms at the maternal-fetal inter-
face. Pyroptosis may occur in the placenta as evidenced by ele-
vated serum levels of active caspase-1 and its substrate or
cleaved products, Gasdermin D, IL-1b, and IL-18, and leads to
severe sterile placental inflammation [57].
For another, placental pyroptosis is a key event that induces
the release of inflammatory factors into maternal circulation that
possibly contribute to severe sterile inflammation and early onset
preeclampsia pathology. NLRP3 inflammasome activation located
at the syncytiotrophoblast layer can also be a possible cause to
the harmful placental inflammation in pre-eclampsia [58].
Pyroptosis-mediated release of inflammatory factors gathers
immune cells, activates excessive inflammatory reactions, dam-
ages endothelial cell, and ultimately leads to the occurrence of
pre-eclampsia [59]. Pre-eclampsia is associated with coagulation,
platelet activation and increased extracellular vesicle formation
[60]. Together with vascular endothelial injury, the over-activa-
tion of sterile inflammation has also been brought to the table as
a main pathogenesis of pre-eclampsia [59]. Recent study shows
that compared with normotensive pregnant women, the NLRP3
inflammasome, caspase-1 and IL-1blevel showed a striking
increase in placentae from pre-eclampsia patients. This result
may indicate the exaggerated inflammatory body state [61] and
the possible involvement of pyroptosis in pre-eclampsia women.
Pyroptosis of trophoblast reduces its invasion, causing a
restricted infiltration and abnormal blood vessels recasting,
which ultimately leads to ischemia and hypoxia at maternal-fetal
interface. Moreover, inhibiting NLRP3 activation and inflamma-
tory cascade in preeclampsia leads to an enhanced migration and
invasion ability [62].
Intraamniotic inflammation has been causally linked to pre-
term birth. The innate immune response required for successful
implantation and placentation is regulated by the a2 isoform of
V-ATPase and the concurrent infiltration of M1 and M2 macro-
phages in the uterus and placenta. Using toll-like receptor 2
agonist, peptidoglycan, and Toll-like receptor 3 agonist, polyino-
sinic-polycytidylic acid [53], the mouse model of gram-positive
bacterial and viral infection-induced preterm delivery can be
simulated. The artificially infected pregnant rats showed a signifi-
cantly decreased expession of V-ATPase as well as an upregu-
lated expression of inducible NO synthase in the placenta,
uterus, and fetal membranes. This imbalance would further cause
simultaneous activation of inordinate inflammatory processes
among uterine decidual cells and spongiotrophoblasts [63]. The
expression of NLRP3 inflammasome and activation of caspase-1
were also increased in drug-induced endometriums [64]. As a
result, the damaged trophoblast cells cannot develop and invade
as required, thus, leading to preterm labor. On the contrary,
when use omega-3 fatty acid to inhibit inflammasome activation
in trophoblasts, preterm labor could be reduced [65], which
GYNECOLOGICAL ENDOCRINOLOGY 3
marks the involvement of pyroptosis in intraamniotic inflamma-
tion induced preterm labor on the other hand.
Other than infections, sterile intraamniotic inflammation is a
special type of chorioamnionitis in which microorganisms cannot
be detected, and is most commonly triggered by cellular stress or
necrotic cells which are recognized as damage-associated molecu-
lar patterns [66]. When compared to the chorioamniotic mem-
branes from puerperae without placental lesion, an upregulation
of NLRP3 level and the active form of caspase-4, can be observed
in the membranes from those who suffered spontaneous preterm
labor with acute histologic chorioamnionitis. The increased ASC/
caspase-1 complex formation participates in the release of IL-1b
and IL-18 and induces pyroptosis in the chorioamniotic mem-
branes [67].
These evidences support the role for inflammasomes taking a
part not only in the physiological inflammation during normal
labor but also in the pathological inflammation implicated in
spontaneous preterm labor. Beyond that, an increased serum
level of IL-18 was observed in premature rupture of membranes,
acute fatty liver of pregnancy and fetal growth restriction [68],
which indicates the state of inflammation in the above men-
tioned diseases.
The application of pyroptosis and inflammasomes in
other diseases shed light on future treatment of GDM
and PCOS
Just as most metabolic diseases, GDM and insulin resistance in
PCOS are both accompanied with a state of chronic low-grade
inflammation [69] and oxidative stress injury. Hence, although
not much has been learnt about the pathogenesis of either two
diseases, we assume that GDM and PCOS insulin resistance may
share common pathogenesis with metabolic diseases.
As mentioned above, the stage of pregnancy is physiologically
associated with a highly regulated chronic, low-grade inflamma-
tory response, and the balance between pro- and anti-inflamma-
tory cytokines is considered vital to the success of implantation,
trophoblast invasion and placentation [70].
Insulin resistance is a common state in physiological pregnan-
cies [71], characterized by a reduction in nearly half of the insu-
lin-mediated glucose clearance. It is followed by a significantly
increased insulin production in order to maintain euglycemia
[72,73]. When it comes to patients with GDM, hyperglycemia
induces chronic stress of the placental, reflecting in a remarkably
increased plasma level of TNF-a, a primary mediator of inflam-
mation and insulin resistance, especially in early and late preg-
nancy. An elevated expression of active caspase-1 and mature IL-
1bsecretion was observed in adipose tissue of women with
GDM, pointing out the activation of inflammasomes. The
inflammasomes interferes with the insulin signaling pathway
leading to the insulin resistance in GDM [74]. The altered
inflammatory profile of the mother may cause changes in placen-
tal nutrient transporter expression and activity [75] Therefore,
pregnant women with obesity or GDM tend to suffer more
severe insulin-resistance compared to normal pregnant
women [76].
Hyperinsulinemia caused by the defection of insulin signaling
pathway manifests as hyperglycemia, and the hyperglycemic
environment is associated with oxidative stress [77]. OS leads to
the over-synthesizing of reactive oxygen species, and GDM
women have been reported to overproduce free radicals and
have impaired free-radical scavenging mechanisms [78]. Recent
studies have shown that reactive oxygen species contributes to
the activation of proinflammatory cytokines and NLRP3 inflam-
masome as well as causing cell injury and prompting insulin
resistance in turn.
Recent studies have shown that most women suffering from
PCOS are usually under a chronic low-grade inflammatory con-
dition [79] featured by a noticable higher concentration of serum
inflammatory factors [80]. These factors include hypersensitive c-
reactive protein, IL-18, TNF-a and PAI-1, as well as a great
amount of macrophages and lymphocytes infiltration in the
ovary [81]. Although the pro-caspase-1 level showed no signifi-
cant change in the PCOS ovary, the activated caspase-1 level
showed a noticeable increase. The infiltration of macrophages in
visceral adipose fat and the increased level of IL-18 may play a
major role in the pathophysiology of insulin resistance [82], as
the latter is also considered as an inflammatory disorder.
The improvement of PCOS insulin sensitivity is related to the
decrease of inflammatory reaction. Metformin treatment has also
been proved to be effective on the symptoms of PCOS. It can
lower the level of blood c-reactive protein and NLRP3 in the
ovary, and therefore easing the low-grade inflammation. Besides,
researches have found that serum IL-18 level appears to be deter-
mined by Body mass index and serum testosterone level as well,
and serum level of testosterone seemed to be the most important
influencing factor. There seems to be a positive correlation
between serum level of IL-18 level and hyperandrogenism.
However, the mechanism of it has not been fully elucidated yet.
One possible mechanism of this could be IL-18 induces the
expression of the key enzymes in the process of androgen syn-
thesis in follicular membrane cells [83]. By stimulating islet beta
cell viability and hyperplasia in the PCOS-like mouse model
[84], adiponectin is considered as a strong factor related to insu-
lin resistance in women with PCOS. Adiponectin reverses the
overexpression of caspase-1, IL-18 and IL-1bin human artificial
episomal chromosome after lipopolysaccharide exposure, and
alleviates NLRP3-inflammasome-mediated pyroptosis of aortic
endothelial cells [85].
Chronic inflammation is a risk factor underlying several
metabolic disorders such as obesity and diabetes. An interesting
theme came to our knowledge from the past few years of
research is that inflammation and metabolism are intimately
linked with one another.
Inflammasomes modulate nutrients metabolism in human
body via several mechanisms [14]. Glycolysis wise, macrophages
containing active inflammasomes appear to have a lower glycoly-
sis rate than the normal ones. Moreover, inflammasomes also
participate in regulating lipid homeostasis by activating caspase-1
[86]. On the one hand, inflammasomes take part in cholesterol
biosynthesis in the liver and triglyceride absorption in the intes-
tine [87]. While on the other end of the balance, when the body
is in a fasting stage or when the host consumes an excess
amount of fatty foods, inflammasomes facilitate the clearance of
triglycerides from the plasma.
Diabetes mellitus is a chronic and continuous inflammatory
state of the body, and targets multiple organs. In diabetes, hyper-
glycemia and saturated fatty acids activates the NLRP3 inflam-
masome, following by the activation of cleaved caspase-1. These
processes lead to the conversion of IL-1bprecursors and IL-18
precursors into their mature forms, causing inflammation of the
islets [88]. As a result, a vicious circle is formed due to the
development of pancreatitis and deranged glycemic control,
which causes a greater range of inflammation. Other than the
classic pathogenesis of the chronic complications of type 2 dia-
betes, which includes altered metabolism, mitochondrial
4 S.-Y. YU AND X.-L. LI
dysfunction, oxidative stress, chronic inflammation, and extracel-
lular matrix remodeling [89], recent studies are suggesting that
pyroptosis is associated with diabetic cardiomyopathy. Moreover,
NLRP3 inflammasome activation is observed in complicating
chronic kidney disease and diabetic nephropathy [90].
Westermann indicated that cardiac dysfunction and inflam-
mation in diabetic cardiomyopathy could be alleviated by a cas-
pase-1 inhibitor [91] and Luo proved that silencing the NLRP3
inflammasome might protect cardiac structures and functions
from the hyperglycemia-induced myocardial cell pyroptosis and
damage [92]. In that case, finding an appropriate method of mit-
igating pyroptosis and inflammation can lead to a promising
therapy in diabetic cardiomyopathy.
Autoimmune diseases, represented by systemic lupus erythe-
matosus is characterized by an autoimmune response against
nuclear antigen of the host, especially the dsDNA. An increased
expression of IL-1bhas been noted in the peripheral blood
mononuclear cells from patients with systemic lupus erythemato-
sus [93]. Serum IgG containing anti-dsDNA along with self
dsDNA activates the NLRP3 inflammasome [94]. These findings
provide new insights into the pathogenesis of autoimmune dis-
eases involving inflammasomes.
Since the innate immune response also plays an important
part in the pathogenic mechanisms of obstetrical and gyneco-
logical diseases including GDM and PCOS insulin resistance,
medical treatments that aim at suppressing pyroptosis and
inflammasomes are potential therapeutic targets. However, only
few current researchs dabble in the field of treating obstetrical
and gynecological diseases by restraining chronic inflammation.
The smooth muscle constrictor methylergometrine mostly
acts on the uterus, and it is currently used during postpartum
hemorrhage to prevent or control excessive bleeding [95].
However, methylergometrine is also considered an inhibitor of
the inflammasome complex in ASC-mediated pro-caspase-1 acti-
vation screening, it can inhibit the activation of NLRP1 and
NLRP3 inflammasomes in cellular models upon different pro-
inflammatory stimuli [96]. Thus, further research could lead to a
promising future of methylergometrine and its anti-inflammatory
effects to suppress pyroptosis in certain diseases.
Researchers found that comparing to normal pregnant rats,
the placenta trophoblastic tissues from pregnant rat models with
preeclampsia showed an activated caspase-1/IL-1binflammatory
pathway while the C1q/tumor necrosis factor related protein 4
expression was downregulated. Simultaneously, treating these
rats with C1q/tumor necrosis factor related protein 4 recombin-
ant protein can inhibit pyroptosis and the caspase-1/IL-1bpath-
way in their trophoblasts, while C1q/tumor necrosis factor
related protein 4 neutralizing antibody treatment had an opposite
effect on pyroptosis and inflammation [97]. The above studies
suggest that inhibiting the caspase-1/IL-1bpathway can be a
feasible approach to suppress pyroptosis and inflammasome acti-
vation, and thus is worthy of further research.
These results show that pyroptosis and inflammasomes not
only play a role in the development of a variety of obstetrical
and gynecological diseases, but also can be a new target of treat-
ment in the near future.
Conclusion
Compared to the numerous studies focusing on infection, meta-
bolic diseases, and autoimmune diseases, the currently known
participation of cell pyroptosis and inflammasomes in the field
of obstetrical and gynecological disorders is only a tip of the
iceberg. Pyroptosis and inflammasomes are confirmed to be
involved in endometriosis and gynecological malignant tumors,
and medical approachs inducing pyroptosis of the ectopic endo-
metrium and cancer cells can be a feasible treatment for endo-
metriosis and gynecological cancers. On the maternal-fetal
interface, although the innate immune response activation is
required for successful implantation and placentation, maternal
and fetal injury may occur once the inflammasomes are over-
activated. Since GDM and PCOS insulin resistance share com-
mon pathogenesis with metabolic diseases, this domain research
sheds light on future study of some obstetrical and gyneco-
logical diseases.
Author contributions
Wrote the manuscript: Shu-Yue Yu, Xue-Lian Li.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This study was supported by Natural Science Foundation from
Science and Technology Commission of Shanghai Municipality
[grant No. 17ZR1403100 to Xue-Lian Li].
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