Inflammation is a defense response induced by potentially harmful stimuli that usually requires the participation of multi-protein complexes known as inflammasome. The NOD-like receptor protein 3 (NLRP3) inflammasome can recognize a variety of pathogenic microorganisms and stress-related endogenous signaling molecules. It is mainly expressed and activated in dendritic cells and macrophages, where it plays an important regulatory role as a pro-inflammatory factor of the host's innate immune system. Many immune and metabolic disorders involve activation of the NLRP3 inflammasome activation,[1,2] such as atherosclerosis, gout, kidney disease, obesity, type 2 diabetes, and inflammatory bowel disease. Some studies suggest that activation of the NLRP3 inflammasome is linked to endometriosis, polycystic ovary syndrome (PCOS), recurrent spontaneous abortion (RSA), preterm birth, pre-eclampsia (PE) and gestational diabetes mellitus (GDM). This article reviews the progress of research into the role of this inflammasome in such reproductive disorders.
Mechanism of NLRP3 Activation
The NLRP3 inflammasome is a member of the nucleotide-binding oligomerization domain, leucine-rich repeat (LRR)-containing protein family. It contains a central nucleotide-binding and oligomerization domain, a C-terminal LRR domain, and an N-terminal pyrin domain. Its activation requires two steps. The first or priming signal, such as lipopolysaccharide (LPS), induces the expression of NLRP3 and Pro-interleukin (IL)-1β and Pro-IL-18. The second activating signal involves many activators, such as cholesterol, uric acid and ATP, and exogenous stimuli such as asbestos, ultraviolet light, pathogenic microorganisms and their metabolites. In this step, the C-terminal senses a variety of endogenous stimuli, and binds to the pyrin domain (PYD) of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) through its N-terminal PYD. Pro-caspase-1 is recruited to self-splice and generate the activated caspase-1 (p10/p20 complex). Activated caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, then the latter two are secreted from cells to activate the downstream inflammatory response.
The mechanisms involved in activating the NLRP3 inflammasome remain unclear. Possible processes include changes in intracellular calcium concentration, lysosomal damage, mitochondrial damage, potassium ion efflux, and reactive oxygen species (ROS) production. The main function of this inflammasome is to initiate assembly of the inflammatory complex, and ASC serves as an adaptor protein of the inflammasome to connect upstream NLRP3 and downstream caspase-1. When the NLRP3 inflammasome becomes over-activated, it induces pyroptosis by generating excessive inflammatory factors and participates in the development of certain diseases.
NLRP3 and Reproductive Disorders
NLRP3 and endometriosis
Endometriosis (EMs) is a common gynecological disease. About 10% to 15% of women of childbearing age exhibit EMs, and about 30% of infertile women are affected by this disease.[10,11] Many recent studies have suggested that immune factors play important roles in its pathogenesis. Hypothyroidism, susceptibility to vaginal candidiasis, auto-immune diseases, fibromyalgia, chronic fatigue syndrome, headaches, arthralgias and myalgias, asthma and allergies are more common comorbidities in women with EMs than in women without it. Therefore, a possible link between endometriosis and autoimmunity has been suggested. Peritoneal fluid samples from women with EMs show defectively activated macrophages and natural killer (NK) cells, which alter the recognition and clearance of endometrial cells. Macrophages secrete different products such as growth factors, enzymes, prostaglandins, and cytokines that stimulate the adhesion of endometrial tissue to mesothelial cells, promoting the invasion of extracellular matrix creating islands of endometrial cells where they can proliferate. Previous studies have shown that inflammation is an important pathophysiological basis for EMs. The intra-abdominal inflammatory environment and immune abnormalities are closely related to ectopic endometrial hyperplasia. Inflammation is a response from living tissues to infection or damage. Bullon et al proposed that abnormal activation of inflammasome is closely related to the occurrence of endometriosis. As an important inflammatory mediator in inflammatory responses, the NLRP3 inflammasome is an important component of inflammasomes. The same study also explored whether the NLRP3 inflammasome acts in the pathogenesis of EMs by establishing an EMs model: when the NLRP3 level was reduced, the production of inflammatory cytokines was inhibited. Ahn et al analyzed the genes associated with inflammation and immunity in patients with endometriosis, including 579 genes involved in human immunity and inflammation and 15 housekeeping genes. They found that 396 genes were upregulated in ectopic endometrial tissues, including those encoding caspase-1, IL-18, and NLRP3.
NLRP3 inflammasomes secrete many inflammatory factors, such as IL-1β, which are associated with the occurrence and development of EMs.[17,18] Bullon et al and Sikora et al reported that the concentrations of IL-1β in the extrauterine tissues and peritoneal fluid from patients with EMs were significantly higher than those from healthy women. Another study suggested that IL-1β upregulates the expression of cyclooxygenase-2 and increased the release of vascular endothelial growth factor (VEGF) in endometrial stromal cells and that this might promote the formation of EMs. Zhao et al found that a large amount of inflammatory cell infiltration occurred in an animal model of EMs compared with a sham-treated group and that the levels of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor [TNF]-α) in the EMs group were significantly higher than in controls.
There are few studies about the treatment of EMs targeting the NLRP3 inflammasome. Thus, the oncogene Astrocyte elevated gene-1 (AEG-1) promoted inflammation in cases of EMs by reducing the cytokine signaling-1 (SOCS1) level and stimulating formation of the NLRP3 inflammasome. While silencing AEG-1 alone increased SOCS1 levels, the levels of inflammatory cytokines decreased, thereby inhibiting the formation of the NLRP3 inflammasome. However, the effects of NLRP3 inhibitors on the occurrence and development of EMs need further study.
NLRP3 and PCOS
PCOS is a common endocrine and metabolic disorder of women of childbearing age, and is associated with cardiovascular diseases, hyperandrogenism, insulin resistance, obesity, metabolic syndrome, and reproductive abnormalities. At present, the etiology of PCOS remains controversial and many studies have suggested that chronic inflammation is involved. Clinical studies have found that factors involved in chronic inflammation, such as ILs, TNF-α, plasminogen activator inhibitor type (PAI)-1, and monocyte chemoattractant protein (MCF)-1, are increased in the peripheral blood of patients with PCOS to varying degrees. Inflammatory factors can lead to the reconstruction of ovarian tissue and alter normal follicular development.[23–25] There is also compelling evidence that the rates of apoptosis of ovarian granulosa cells (GCs) in antral follicles in women with PCOS are significantly increased compared with healthy controls. Wang et al suggested that hyperandrogenism is the main cause of infertility as a result of PCOS, hyperandrogenism can drive the generation of the NLRP3 inflammasome, which results in the secretion of inflammatory mediators, and induced low-grade inflammation in mice with PCOS. Some women with PCOS appear to have increased levels of androgen, oxidative stress, free fatty acid (FFA) and high-mobility group box 1 (HMGB1), molecules that serve as danger signals to activate the inflammasome pathway, especially the NLRP3 inflammasome pathway.
During the development of PCOS, follicular dysfunction and anovulation are closely linked to ovarian fibrosis. Thus, affected patients manifest with increased cystic follicles, a thickened thecal cell layer, loose arrangements of GCs, and reduced corpus luteum formation, which has also been replicated in animal models of PCOS.[29,30] Activation of the NLRP3 inflammasome accelerates ovarian fibrosis in mice with PCOS. Thus, the NLRP3 inflammasome is implicated as a potential target in the prevention of ovarian fibrosis. When GCs were treated with INF39, a specific inhibitor of NLRP3, the ovarian fibrosis indexes such as the levels of alpha smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), TGF-β were suppressed and ovarian interstitial fibrosis was remarkably reduced.
Activation of the NLRP3 inflammasome results in activation of caspase-1, which in turn promotes the production of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, respectively. Such cytokines play important roles in regulating ovarian steroidogenesis, maturation of ovarian follicles, and other reproductive processes, and the expression of IL-18 was significantly increased in patients with PCOS. In addition, IL-1β is involved in the development of obesity-related insulin resistance and macrophage adipocyte crosstalk. IL-1β impairs the insulin sensitivity of adipose tissue by inhibiting insulin signaling, so blocking its activity or production might enhance insulin signaling. In addition, IL-1β stimulates lipolysis and increases body weight by inhibiting the expression of fatty acid translocases and fatty acid transporters. These studies have suggested that IL-1β might be protectively involved in the onset and progression of weight gain. In addition, Guo et al found that the pioglitazone metformin complex preparation could reduce inflammation, inhibit activation of the NLRP3 inflammasome, and reduce the release of IL-1β in the treatment of PCOS.
However, further experiments are still needed to clarify the exact role of NLRP3 inflammasomes in PCOS, and such studies may lead to new treatments and managements for this disease.
NLRP3 and RSA
The causes of RSA are very complex. Many factors including anatomy, endocrine, genes, immunity and infection are considered to be involved.[35,36] Only about 30% of cases of RSA have a clear cause, and many unrecognized cases are believed to be related to abnormal immune and inflammatory responses.[37,38]
RSA is considered to reflect an allogeneic transplantation process. The balance of anti- and pro-inflammatory factors at the maternal-fetal interface plays an important role in maintaining pregnancy, and most inflammation requires the participation of inflammasomes. A significantly increased expression of the endometrial NLRP3 inflammasome, and of caspase-1-dependent secretion of IL-1β and IL-18 were demonstrated in endometrial tissues obtained from women with RSA compared with a control group (fertile women).[39,40] Thus, the NLRP3 inflammasome might represent a novel family of marker proteins of endometrial receptivity. Abnormal inflammasome activation, might be one of the molecular mechanisms involved in establishing an unreceptive endometrium, which potentially leads to early fetal loss. Tersigni et al also found that the intestinal permeability of patients with RSA was increased abnormally, and that the expression levels of caspase-1, IL-1β, and NLRP3 in endometrial tissue were increased significantly. They speculated that women with RSA might have a leaky gut, which could induce an endometrial immune response, and lead to recurrent miscarriage. In vitro cell experiments showed that administration of palmitic acid or antiphospholipid antibodies activated NLRP3 inflammasomes in normal early gestational trophoblast cells, and increased the expression of IL-1β,[42,43] indicating that the abnormal inflammatory reaction caused by NLRP3 inflammasomes might be linked to RSA. As is well known, regulatory T (Treg) and Th17 cells play important roles in the pathogenesis of RSA,[44–46] and Lu et al reported that activated NLRP3 inflammasomes participate in the pathogenesis of RSA by regulating the balance of Th17 and Treg cells.
Because NLRP3 is involved in several inflammatory diseases, there is significant interest in the discovery of beneficial therapeutics that could selectively inhibit its activation. MCC950 is a selective, potent, small-molecule inhibitor of the NLRP3 inflammasome. It inhibits NLRP3-induced ASC oligomerization in mouse and human macrophages. Beta-hydroxybutyrate is another inflammasome inhibitor, that can reduce caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases. Micro RNAs (miRs) such as miR 223 and miR 9 are both reported to inhibit activation of the NLRP3 inflammasome. Furthermore, several herbal extracts and their bioactive constituents are effective in mediating the inflammatory response caused by activation of the NLRP3 inflammasome, such as resveratrol, arglabin, and extracts from Morus bombycis.
However, efficacious inflammasome inhibitors for use in clinical studies are still at an early stage of development and high-quality studies are needed to evaluate the effectiveness and safety of these drugs for unexplained RSA.
NLRP3 and preterm birth
Human childbirth is a complex process and its initiation remains unclear. Preterm birth is one of the most common, yet detrimental, obstetric syndromes. Approximately 70% of all preterm births are preceded by spontaneous preterm labor. Of all the putative causes associated with spontaneous preterm labor, only intraamniotic inflammation/infection has been linked causally to preterm birth.[56–58] Pregnancy-related tissues such as uterine muscle, fetal membranes, and placenta all express NLRP3 inflammasomes. Gomez-Lopez et al found that women with spontaneous preterm labor and acute chorioamnionitis had activated NLRP3 inflammasomes in chorionic tissues and significantly increased levels of the active form of caspase-1 and mature forms of IL-1β and IL-18, indicating that abnormal activation of NLRP3 in spontaneous preterm labor was caused by acute chorioamnionitis. The expressions of inflammasome-related genes (eg, those encoding NLRP3, caspase-1, and IL-1β) were upregulated in the chorioamnionitis membranes of women who underwent spontaneous preterm labor compared with women who delivered preterm without this placental lesion. In an animal model of lipopolysaccharide-induced intra-amniotic inflammation, NLRP3 was activated in the fetal membrane before premature delivery, and higher IL-1β protein levels were released in the base of the fetal membrane, the decidual membranes and amniotic fluid.
Many recent studies found that pro-inflammatory cytokines, such as IL-1β, the main products of NLRP3 activation, promote the production of prostaglandin synthetase-2 (PGHS-2), as well as the secretion of more prostaglandins via the effect of PGHS-2. Prostaglandins are important regulators of cervical ripening and increase significantly during delivery. One study found that the expression levels of IL-β, IL-6, IL-8, and TNF-α were all significantly increased in the chorionic and amniotic membranes of women undergoing preterm labor. IL-1β, IL-6 and TNF-α mRNA and protein levels were significantly elevated in uterine muscle during labor, and these cytokines stimulate the synthesis of interstitial metalloproteinases in the endometrium and amniotic sac.
Importantly, the NLRP3 inflammasome might be a therapeutic target for preventing preterm birth. The study found that the intra-amniotic administration of the alarmin S100B could activate the NLRP3 inflammasome in fetal membranes, increase the levels of the NLRP3 sensor molecule, active caspase-1, and mature IL-1β, then induce preterm labor/birth with adverse neonatal outcomes. Inhibition of the NLRP3 inflammasome via the specific inhibitor MCC950 prevented preterm labor/birth and reduced neonatal mortality.[61,64] Faro et al reported that the use of MCC950 could extend gestational length and not only reduce the rate of intra-amniotic inflammation-induced preterm birth by 30%, but can significantly improve neonatal survival as well in mouse. Moreover, a preliminary study provided evidence that MCC950 could be safe for clinical use in humans. However, the inhibition of the NLRP3 inflammasome at term does not obstruct the physiological process of parturition.
Therefore, we suggest that targeting NLRP3 activation might provide one avenue to reduce the incidence of preterm birth and improve neonatal outcomes.
NLRP3 and PE
PE is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria and fetal intrauterine growth restriction. Pathophysiological changes in PE include inflammation and immune cell activation.[66–68] The placenta clearly plays a central role in the pathogenesis of PE as demonstrated by the rapid disappearance of disease symptoms after delivery. Thus, placenta-derived circulating factors might induce excessive inflammation and endothelial defects, which leads to PE. Mulla et al and Xie et al were the first to demonstrate that activation of the NLRP3 inflammasome in trophoblasts and peripheral blood was implicated in the pathogenesis of PE. Since then, there has been a rapid increase in reports that the NLRP3 inflammasome is involved in the pathogenesis of PE.[72–76] Thus, there was significantly higher expression of NLRP3 and related mediators such as caspase-1, IL-1β, and IL-18 in samples from women with PE compared with controls. Moreover, Xu et al and Pontillo et al reported that specific NLRP3 gene polymorphisms are associated with a significantly higher risk of PE. Omi et al examined 1911 patients (987 with hypertension and 924 controls) and found that homozygotes carriers of high activity NLRP3 alleles that produce more chemokines after stimulation, had a greater risk of developing hypertension compared with both heterozygote and homozygote carrier of low activity NLRP3 alleles. These results suggest that the placentas of pregnant women with PE show higher expression of NLRP3 inflammasomes, which may be related to the significantly upregulated inflammation state in PE. Thus, NLRP3 inflammasome activity has an important role in the development of PE.
Are there some specific triggers during activation of NLRP3 in PE? In affected patients, many endogenous danger/damage-associated molecular patterns (DAMPs), such as, cholesterol, uric acid crystals, extracellular DNA, HMGB1 proteins, extracellular cell debris, free fatty acids, and advanced glycation end-products, have been detected at higher levels in the peripheral blood and placenta and act as NLRP3 inflammasome activators.[80–99] These DAMPs induced the cytosolic leakage of cathepsin B via lysosomal rupture. Leakage of cathepsin B also leads to potassium efflux and mitochondrial damage. Potassium efflux and reduced intracellular potassium concentrations result in activation of the NLRP3 inflammasome.
In an in vitro human placental explant experiment, treatment with cholesterol crystals significantly increased the release of IL-1β, and was suppressed by treatment with MCC950, a specific inhibitor of the NLRP3 inflammasome. Allopurinol is a xanthine oxidase inhibitor that inhibits uric acid and reactive oxygen species (ROS) production. Negi et al reported that allopurinol could significantly inhibit trophoblast secretion of inflammatory IL-1β and caspase-1 activity. Thus, allopurinol could be a candidate medication to prevent placental dysfunction and adverse pregnancy outcomes, such as PE. Moreover, Park et al found that antioxidants such as resveratrol and N-acetylcysteine could inhibit the expression of NLRP3 protein and caspase-1 activation in trophoblast cells. They might represent suitable therapeutic options for the treatment of inflammation-associated pregnancy complications.
The above findings suggest that the NLRP3 inflammasome plays a crucial role in the development of PE, so inhibitors could be very effective treatments. However, more detailed research is still needed to confirm this possibility in the prevention and treatment of PE by targeting NLRP3.
NLRP3 and GDM
GDM is a metabolic disorder in pregnant women characterized by glucose intolerance during the second or third trimester of pregnancy. GDM can harm pregnancy outcomes and the long-term health and wellbeing of offspring. Under all hyperglycemic conditions, maternal plasma and placental levels of inflammatory factors (IL-1β, IL-6, and monocyte chemoattractant protein-1) increased, and ASC, caspase-1, NLRP1, and NLRP3 were upregulated in all hyperglycemic groups. Chronic proinflammatory cytokines are considered to be pathologic mediators of diabetogenic metabolic disorders, associated with insulin resistance and pancreatic islet cell death.[107–110] In patients with GDM, studies have proved a connection between activation of the NLRP3 inflammasome and insulin resistance. High glucose levels increase NLRP3 activation compared with those induced by normal and low glucose levels. It is known that hyperglycemia or diabetes during pregnancy can induce activation of the NLRP3 inflammasome and the secretion of many inflammatory cytokines, which results in severely adverse pregnancy complications.
Therefore, how to inhibit activated inflammasomes could be an important consideration when managing hyperglycemia and preventing adverse pregnancy outcomes. Glombik et al observed that maternal diabetes causes the activation of NLRP3 inflammasome signaling by increasing the level of the NLRP3 protein subunit, and glyburide, as a NLRP3 inflammasome inhibitor, diminishes the level of NLRP3 protein and caspase-1 subunits, and has particular therapeutic value in anti- metabolic-related inflammation. Zhang et al found that astragaloside IV (AS-IV) treatment was an effective therapy for GDM in a mouse model through the inhibition of NLRP3 inflammasome in the pancreas. Negi et al reported allopurinol significantly inhibited NLRP3 activation, inhibited trophoblast secretion of inflammatory IL-1β; caspase-1 activity, reduced additional pro-inflammatory and anti-angiogenic responses to excess glucose, prevent placental dysfunction and adverse pregnancy outcomes in patients with GDM. Therefore, this inflammasome represent a useful therapeutic target in the treatment of GDM.
In summary, the NLRP3 inflammasome plays an important role in high-risk reproductive disorders, and can cause infertility, miscarriage and many pregnancy complications. Understanding how the NLRP3 inflammasome regulates pregnancy complications and how to control excessive NLRP3 inflammasome activation is essential for the identification of new targets for the treatment of reproductive dysfunction. Thus, NLRP3 inflammatory complex inhibitors have certain therapeutic options for treating related diseases. However, we still need more research to understand the pathogenesis and to develop the mechanism-specific and safe treatments for reproductive disorders.
The work was supported by grants from the National Key Research and Development Program of China (No. 2018YFC1004800) and The Medical and Health Program in Zhejiang Province (No. 2019KY411).
Conflicts of interest
1. Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol
2016; 13:148–159. doi: 10.1038/cmi.2015.95.
2. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol
2015; 6:262doi: 10.3389/fphar.2015.00262.
3. Wang Y, Kong H, Zeng X, Liu W, Wang Z, Yan X, et al. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol Rep
2016; 35:2053–2064. doi: 10.3892/or.2016.4569.
4. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol
2013; 13:397–411. doi: 10.1038/nri3452.
5. Rossol M, Pierer M, Raulien N, Quandt D, Meusch U, Rothe K, et al. Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat Commun
2012; 3:1329doi: 10.1038/ncomms2339.
6. Hornung V, Latz E. Critical functions of priming and lsosomal damage for NLRP3 activation. Eur J Immunol
2010; 40:620–623. doi: 10.1002/eji.200940185.
7. Lyu JJ, Mehta JL, Li Y, Ye L, Sun SN, Sun HS, et al. Mitochondrial autophagy and NLRP3 inflammasome in pulmonary tissues from severe combined immunodeficient mice after cardiac arrest and cardiopulmonary resuscitation. Chin Med J
2018; 131:1174–1184. doi: 10.4103/0366-6999.231519.
8. Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ
2007; 14:1583–1589. doi: 10.1038/sj.cdd.4402195.
9. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature
2011; 469:221–225. doi: 10.1038/nature09663.
10. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann NY Acad Sci
2002; 955:11–22. discussion 34-36, 396-406. doi: 10.1111/j.1749-6632.2002.tb02761.x.
11. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril
2004; 81:1441–1446. doi: 10.1016/j.fertnstert.2004.01.019.
12. Bullon P, Navarro JM. Inflammasome as a key pathogenic mechanism in endometriosis. Curr Drug Targets
2017; 18:997–1002. doi: 10.2174/1389450117666160709013850.
13. Bulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, et al. Role of estrogen receptor-β in endometriosis. Semin Reprod Med
2012; 30:39–45. doi: 10.1055/s-0031-1299596.
14. Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update
2019; 25:473–485. doi: 10.1093/humupd/dmz005.
15. Mezzasoma L, Antognelli C, Talesa VN. A novel role for brain natriuretic peptide: inhibition of IL-1β secretion via downregulation of NF-kB/Erk 1/2 and NALP3/ASC/Caspase-1 activation in human THP-1 monocyte. Mediators Inflamm
2017; 2017:e5858315doi: 10.1155/2017/5858315.
16. Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M, Tayade C. Immune-inflammation gene signatures in endometriosis patients. Fertil Steril
2016; 106:1420–1431. doi: 10.1016/j.fertnstert.2016.07.005.
17. Sikora J, Smycz-Kubańska M, Mielczarek-Palacz A, Bednarek I, Kondera-Anasz Z. The involvement of multifunctional TGF-β and related cytokines in pathogenesis of endometriosis. Immunol Lett
2018; 201:31–37. doi: 10.1016/j.imlet.2018.10.011.
18. Patel BG, Lenk EE, Lebovic DI, Shu Y, Yu J, Taylor RN. Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways. Best Pract Res Clin Obstet Gynaecol
2018; 50:50–60. doi: 10.1016/j.bpobgyn.2018.01.006.
19. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Imbalance in cytokines from interleukin-1 family - role in pathogenesis of endometriosis. Am J Reprod Immunol
2012; 68:138–145. doi: 10.1111/j.1600-0897.2012.01147.
20. Huang F, Cao J, Liu Q, Zou Y, Li H, Yin T. MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1β induced in human endometriosis stromal cells in vitro. Int J Clin Exp Pathol
21. Zhao J, Ma W, Chen WZ, Gao J, Li C, Tong Y, et al. AEG-1 aggravates inflammation via promoting NALP3 inflammasome formation in murine endometriosis lesions. Anim Cells Syst (Seoul)
2019; 23:407–413. doi: 10.1080/19768354.2019.1691052.
22. Jamilian M, Foroozanfard F, Kavossian E, Aghadavod E, Amirani E, Mahdavinia M, et al. Carnitine and chromium co-supplementation affects mental health, hormonal, inflammatory, genetic, and oxidative stress parameters in women with polycystic ovary syndrome. J Psychosom Obstet Gynaecol
2019; 1–9. doi: 10.1080/0167482X.2018.1557144.
23. Rudnicka E, Kunicki M, Suchta K, Machura P, Grymowicz M, Smolarczyk R. Inflammatory markers in women with polycystic ovary syndrome. Biomed Res Int
2020; 2020:4092470doi: 10.1155/2020/4092470.
24. Gholinezhad M, Gholsorkhtabaramiri M, Esmaeilzadeh S, Ghanbarpour A. Insulin resistance and adverse metabolic profile in overweight/obese and normal weight of young women with polycystic ovary syndrome. Caspian J Intern Med
2018; 9:260–267. doi: 10.22088/cjim.9.3.260.
25. Kanafchian M, Esmaeilzadeh S, Mahjoub S, Rahsepar M, Ghasemi M. Status of serum copper, magnesium, and total antioxidant capacity in patients with polycystic ovary syndrome. Biol Trace Elem Res
2020; 193:111–117. doi: 10.1007/s12011-019-01705-7.
26. Paixão L, Ramos RB, Lavarda A, Morsh DM, Spritzer PM. Animal models of hyperandrogenism and ovarian morphology changes as features of polycystic ovary syndrome: a systematic review. Reprod Biol Endocrinol
2017; 15:12doi: 10.1186/s12958-017-0231-z.
27. Wang D, Weng Y, Zhang Y, Wang R, Wang T, Zhou J, et al. Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice. Sci Total Environ
2020; 745:141049doi: 10.1016/j.scitotenv.2020.141049.
28. Rostamtabar M, Esmaeilzadeh S, Karkhah A, Amiri M, Rahmani A, Bakouei F, et al. Elevated expression of IL-18 but not IL-1β gene is associated with NALP3 and AIM2 inflammasome in Polycystic Ovary Syndrome. Gene
2020; 731:144352doi: 10.1016/j.gene.2020.144352.
29. Zhang S, Tu H, Zhu J, Liang A, Huo P, Shan K, et al. Dendrobium nobile Lindl. polysaccharides improve follicular development in PCOS rats. Int J Biol Macromol
2020; 149:826–834. doi: 10.1016/j.ijbiomac.2020.01.196.
30. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol
2018; 14:270–284. doi: 10.1038/nrendo.2018.24.
31. Salmassi A, Fattahi A, Nouri M, Hedderich J, Schmutzler AG. Expression of mRNA and protein of IL-18 and its receptor in human follicular granulosa cells. J Endocrinol Invest
2017; 40:447–454. doi: 10.1007/s40618-016-0590-x.
32. Gao D, Madi M, Ding C, Fok M, Steele T, Ford C, et al. Interleukin-1beta mediates macrophage-induced impairment of insulin signaling in human primary adipocytes. Am J Physiol Endocrinol Metab
2014; 307:E289–304. doi: 10.1152/ajpendo.00430.2013.
33. Bing C. Is interleukin-1beta a culprit in macrophage-adipocyte crosstalk in obesity? Adipocyte
2015; 4:149–152. doi: 10.4161/21623945.2014.979661.
34. Guo QJ, Shan J, Xu YF, Hu YY, Huo CL, Song JY, et al. Pioglitazone metformin complex improves polycystic ovary syndrome comorbid psychological distress via inhibiting NLRP3 inflammasome activation: a prospective clinical study. Mediators Inflamm
2020; 2020:3050487doi: 10.1155/2020/3050487.
35. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J
2015; 91:1511–1562. doi: 10.1136/postgradmedj-2014-132672.
36. Homer HA. Modern management of recurrent miscarriage. Aust N Z J Obstet Gynaecol
2019; 59:36–44. doi: 10.1111/ajo.12920.
37. Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev
2014; 2014:CD000112doi: 10.1002/14651858.
38. Christiansen OB, Larsen EC, Egerup P, Lunoee L, Egestad L, Nielsen HS. Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial. BJOG
2015; 122:500–508. doi: 10.1111/1471-0528.13192.
39. Bauernfeind F, Bartok E, Rieger A, Franchi L, Núñez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol
2011; 187:613–617. doi: 10.4049/jimmunol.1100613.
40. D’Ippolito S, Tersigni C, Marana R, Di Nicuolo F, Gaglione R, Rossi ED, et al. Inflammosome in the human endometrium: further step in the evaluation of the “Maternal Side”. Fertil Steril
2016; 105:111–118. doi: 10.1016/j.fertnstert.2015.09.027.
41. Tersigni C, D’Ippolito S, Di Nicuolo F, Marana R, Valenza V, Masciullo V, et al. Recurrent pregnancy loss is associated to leaky gut: a novel pathogenic model of endometrium inflammation? J Transl Med
2018; 16:102doi: 10.1186/s12967-018-1482-y.
42. Shirasuna K, Takano H, Seno K, Ohtsu A, Karasawa T, Takahashi M, et al. Palmitic acid induces interleukin-1β secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells. J Reprod Immunol
2016; 116:104–112. doi: 10.1016/j.jri.2016.06.001.
43. Mulla MJ, Salmon JE, Chamley LW, Brosens JJ, Boeras CM, Kavathas PB, et al. A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1beta production by human first trimester trophoblast. PLoS One
2013; 8:e65237doi: 10.1371/journal.pone.0065237.
44. Alijotas-Reig J, Melnychuk T, Gris JM. Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: new therapeutic challenging opportunities. Med Clin (Barc)
2015; 144:265–268. doi: 10.1016/j.medcli.2014.01.033.
45. Saito S, Nakashima A, Myojo-Higuma S, Shiozaki A. The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J Reprod Immunol
2008; 77:14–22. doi: 10.1016/j.jri.2007.04.007.
46. Zhu XY, Zhou YH, Wang MY, Jin LP, Yuan MM, Li DJ. Blockade of CD86 signaling facilitates a Th2 bias at the maternal-fetal interface and expands peripheral CD4+CD25+ regulatory T cells to rescue abortion-prone fetuses. Biol Reprod
2005; 72:338–345. doi: 10.1095/biolreprod.104.034108.
47. Lu M, Ma F, Xiao J, Yang L, Li N, Chen D. NLRP3 inflammasome as the potential target mechanism and therapy in recurrent spontaneous abortions. Mol Med Rep
2019; 19:1935–1941. doi: 10.3892/mmr.2019.9829.
48. Perregaux DG, McNiff P, Laliberte R, Hawryluk N, Peurano H, Stam E, et al. Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors. J Pharmacol Exp Ther
49. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med
2015; 21:248–255. doi: 10.1038/nm.3806.
50. Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med
2017; 214:1737–1752. doi: 10.1084/jem.20160462.
51. Wang Y, Han Z, Fan Y, Zhang J, Chen K, Gao L, et al. MicroRNA-9 inhibits NLRP3 inflammasome activation in human atherosclerosis inflammation cell models through the JAK1/STAT signaling pathway. Cell Physiol Biochem
2017; 41:1555–1571. doi: 10.1159/000470822.
52. Chang YP, Ka SM, Hsu WH, Chen A, Chao LK, Lin CC, et al. Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. J Cell Physiol
2015; 230:1567–1579. doi: 10.1002/jcp.24903.
53. Abderrazak A, Couchie D, Mahmood DF, Elhage R, Vindis C, Laffargue M, et al. Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet. Circulation
2015; 131:1061–1070. doi: 10.1161/CIRCULATIONAHA.114.013730.
54. Oh NH, Han JW, Shim DW, Sim EJ, Koppula S, Kwak SB, et al. Anti-inflammatory properties of Morus bombycis Koidzumi via inhibiting IFN-β signaling and NLRP3 inflammasome activation. J Ethnopharmacol
2015; 176:424–428. doi: 10.1016/j.jep.2015.11.022.
55. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet
2008; 371:75–84. doi: 10.1016/S0140-6736(08)60074-4.
56. Oh KJ, Hong JS, Romero R, Yoon BH. The frequency and clinical significance of intra-amniotic inflammation in twin pregnancies with preterm labor and intact membranes. J Matern Fetal Neonatal Med
2019; 32:527–541. doi: 10.1080/14767058.2017.1384460.
57. Kim SM, Romero R, Lee J, Mi Lee S, Park CW, Shin Park J, et al. The frequency and clinical significance of intra-amniotic inflammation in women with preterm uterine contractility but without cervical change: do the diagnostic criteria for preterm labor need to be changed? J Matern Fetal Neonatal Med
2012; 25:1212–1221. doi: 10.3109/14767058.2011.629256.
58. Gomez-Lopez N, Vadillo-Perez L, Hernandez-Carbajal A, Godines-Enriquez M, Olson DM, Vadillo-Ortega F. Specific inflammatory microenvironments in the zones of the fetal membranes at term delivery. Am J Obstet Gynecol
2011; 205:235e15-24. doi: 10.1016/j.ajog.2011.04.019.
59. Koga K, Mor G. Expression and function of toll-like receptors at the maternal-fetal interface. Reprod Sci
2008; 15:231–242. doi: 10.1177/1933719108316391.
60. Gomez-Lopez N, Romero R, Xu Y, Plazyo O, Unkel R, Leng Y, et al. A Role for the inflammasome in spontaneous preterm labor with acute histologic chorioamnionitis. Reprod Sci
2017; 24:1382–1401. doi: 10.1177/1933719116687656.
61. Faro J, Romero R, Schwenkel G, Garcia-Flores V, Arenas-Hernandez M, Leng Y, et al. Inflammation-Induced Intra-Amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome. Biol Reprod
2019; 100:1290–1305. doi: 10.1093/biolre/ioy261.
62. Young A, Thomson AJ, Ledingham M, ordan F, Greer IA, Norman JE. Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod
2002; 66:445–459. doi: 10.1095/biolreprod66.2.445.
63. McLaren J, Taylor DJ, Bell SC. Prostaglandin E(2)-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes. Mol Hum Reprod
2000; 6:1033–1040. doi: 10.1093/molehr/6.11.1033.
64. Gomez-Lopez N, Romero R, Garcia-Flores V, Leng Y, Miller D, Hassan SS, et al. Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes. Biol Reprod
2019; 100:1306–1318. doi: 10.1093/biolre/ioy264.
65. Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A
2018; 115:E1530–E1539. doi: 10.1073/pnas.1716095115.
66. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol
1998; 179:80–86. doi: 10.1016/s0002-9378(98)70254-6.
67. Melgert BN, Spaans F, Borghuis T, Klok PA, Groen B, Bolt A, et al. Pregnancy and preeclampsia affect monocyte subsets in humans and rats. PLoS One
2012; 7:e45229doi: 10.1371/journal.pone.0045229.
68. Lau SY, Guild SJ, Barrett CJ, Chen Q, McCowan L, Jordan V, et al. Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis. Am J Reprod Immunol
2013; 70:412–427. doi: 10.1111/aji.12138.
69. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol
1989; 161:1200–1204. doi: 10.1016/0002-9378(89)90665-0.
70. Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, et al. Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia. Am J Reprod Immunol
2011; 65:542–548. doi: 10.1111/j.1600-0897.2010.00960.x.
71. Xie F, Hu Y, Turvey SE, Magee LA, Brunham RM, Choi KC, et al. Toll-like receptors 2 and 4 and the cryopyrin inflammasome in normal pregnancy and preeclampsia. BJOG
2010; 117:99–108. doi: 10.1111/j.1471-0528.2009.02428.x.
72. Matias ML, Romao M, Weel IC, Ribeiro VR, Nunes PR, Borges VT, et al. Endogenous and uric acid-induced activation of NLRP3 inflammasome in pregnant women with preeclampsia. PLoS One
2015; 10:e0129095doi: 10.1371/journal.pone.0129095.
73. Weel C, Romão-Veiga I, Matias M, Fioratti ML, Peraçoli EG, Borges JC, et al. Increased expression of NLRP3 inflammasome in placentas from pregnant women with severe preeclampsia. J Reprod Immunol
2017; 123:40–47. doi: 10.1016/j.jri.2017.09.002.
74. Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, et al. Uric acid induces trophoblast IL-1beta production via the inflammasome: implications for the pathogenesis of preeclampsia. Am J Reprod Immunol
2011; 65:542–548. doi: 10.1111/j.1600-0897.2010.00960.x.
75. Shirasuna K, Usui F, Karasawa T, Kimura H, Kawashima A, Mizukami H, et al. Nanosilica-induced placental inflammation and pregnancy complications: different roles of the inflammasome components NLRP3 and ASC. Nanotoxicology
2015; 9:554–567. doi: 10.3109/17435390.2014.956156.
76. Tamura K, Ishikawa G, Yoshie M, Ohneda W, Nakai A, Takeshita T, et al. Glibenclamide inhibits NLRP3 inflammasome-mediated IL-1beta secretion in human trophoblasts. J Pharmacol Sci
2017; 135:89–95. doi: 10.1016/j.jphs.2017.09.032.
77. Xu L, Li S, Liu Z, Jiang S, Wang J, Guo M, Zhao X, et al. The NLRP3 rs10754558 polymorphism is a risk factor for preeclampsia in a Chinese Han population. J Matern Fetal Neonatal Med
2019; 32:1792–1799. doi: 10.1080/14767058.2017.1418313.
78. Pontillo A, Reis EC, Bricher PN, Vianna P, Diniz S, Fernandes KS, et al. NLRP1 L155H polymorphism is a risk Factor for preeclampsia development. Am J Reprod Immunol
2015; 73:577–581. doi: 10.1111/aji.12353.
79. Omi T, Kumada M, Kamesaki T, Okuda H, Munkhtulga L, Yanagisawa Y, et al. An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension. Eur J Hum Genet
2006; 14:1295–1305. doi: 10.1038/sj.ejhg.5201698.
80. Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, Kisielow J, et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol
2011; 41:2040–2051. doi: 10.1002/eji.201041316.
81. Stodle GS, Silva GB, Tangeras LH, Gierman LM, Nervik I, Dahlberg UE, et al. Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts. Clin Exp Immunol
2018; 193:84–94. doi: 10.1111/cei.13130.
82. Girard S, Heazell AE, Derricott H, Allan SM, Sibley CP, Abrahams VM, et al. Circulating cytokines and alarmins associated with placental inflammation in high-risk pregnancies. Am J Reprod Immunol
2014; 72:422–434. doi: 10.1111/aji.12274.
83. Brien ME, Duval C, Palacios J, Boufaied I, Hudon-Thibeault AA, Nadeau-Vallee M, et al. Uric acid crystals induce placental inflammation and alter trophoblast function via an IL-1-dependent pathway: implications for fetal growth restriction. J Immunol
2017; 198:443–451. doi: 10.4049/jimmunol.1601179.
84. Pan J, Ou Z, Cai C, Li P, Gong J, Ruan XZ, et al. Fatty acid activates NLRP3 inflammasomes in mouse kupffer cells through mitochondrial DNA release. Cell Immunol
2018; 332:111–120. doi: 10.1016/j.cellimm.2018.08.006.
85. Sur Chowdhury C, Hahn S, Hasler P, Hoesli I, Lapaire O, Giaglis S. Elevated levels of total cell-free DNA in maternal serum samples arise from the generation of neutrophil extracellular traps. Fetal Diagn Ther
2016; 40:263–267. doi: 10.1159/000444853.
86. Yao X, Jiang Q, Ding W, Yue P, Wang J, Zhao K, et al. Interleukin 4 inhibits high mobility group box-1 protein-mediated NLRP3 inflammasome formation by activating peroxisome proliferator-activated receptor-γ in astrocytes. Biochem Biophys Res Commun
2019; 509:624–631. doi: 10.1016/j.bbrc.2018.11.145.
87. Kim EJ, Park SY, Baek SE, Jang MA, Lee WS, Bae SS, et al. HMGB1 increases IL-1beta production in vascular smooth muscle cells via NLRP3 inflammasome. Front Physiol
2018; 9:313doi: 10.3389/fphys.2018.00313.
88. Deng M, Tang Y, Li W, Wang X, Zhang R, Zhang X, et al. The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis. Immunity
2018; 49:740–753. e7. doi: 10.1016/j.immuni.2018.08.016.
89. Iriyama T, Sun K, Parchim NF, Li J, Zhao C, Song A, et al. Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia. Circulation
2015; 131:730–741. doi: 10.1161/CIRCULATIONAHA.114.013740.
90. Baron L, Gombault A, Fanny M, Villeret B, Savigny F, Guillou N, et al. The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine. Cell Death Dis
2015; 6:e1629doi: 10.1038/cddis.2014.576.
91. Boisrame-Helms J, Meziani F, Sananes N, Boisrame T, Langer B, Schneider F, et al. Detrimental arterial inflammatory effect of microparticles circulating in preeclamptic women: ex vivo evaluation in human arteries. Fundam Clin Pharmacol
2015; 29:450–461. doi: 10.1111/fcp.12136.
92. Kohli S, Ranjan S, Hoffmann J, Kashif M, Daniel EA, Al-Dabet MM, et al. Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts. Blood
2016; 128:2153–2164. doi: 10.1182/blood-2016-03-705434.
93. L’Homme L, Esser N, Riva L, Scheen A, Paquot N, Piette J, et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res
2013; 54:2998–3008. doi: 10.1194/jlr.M037861.
94. Shirasuna K, Takano H, Seno K, Ohtsu A, Karasawa T, Takahashi M, et al. Palmitic acid induces interleukin-1beta secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells. J Reprod Immunol
2016; 116:104–112. doi: 10.1016/j.jri.2016.06.001.
95. Robinson NJ, Minchell LJ, Myers JE, Hubel CA, Crocker IP. A potential role for free fatty acids in the pathogenesis of preeclampsia. J Hypertens
2009; 27:1293–1302. doi: 10.1097/hjh.0b013e328329fbfe.
96. Ortega-Senovilla H, Alvino G, Taricco E, Cetin I, Herrera E. Enhanced circulating retinol and non-esterified fatty acids in pregnancies complicated with intrauterine growth restriction. Clin Sci (Lond)
2009; 118:351–358. doi: 10.1042/CS20090292.
97. Marchi J, Berg M, Dencker A, Olander EK, Begley C. Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes Rev
2015; 16:621–638. doi: 10.1111/obr.12288.
98. Alexander KL, Mejia CA, Jordan C, Nelson MB, Howell BM, Jones CM, et al. Differential receptor for advanced glycation end products expression in preeclamptic, intrauterine growth restricted, and gestational diabetic placentas. Am J Reprod Immunol
2016; 75:172–180. doi: 10.1111/aji.12462.
99. Chen W, Zhang Y, Yue C, Ye Y, Chen P, Peng W, et al. Accumulation of advanced glycation end products involved in inflammation and contributing to severe preeclampsia, in maternal blood, umbilical blood and placental tissues. Gynecol Obstet Invest
2017; 82:388–397. doi: 10.1159/000448141.
100. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature
2006; 440:237–241. doi: 10.1038/nature04516.
101. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature
2012; 481:278–286. doi: 10.1038/nature10759.
102. Matias ML, Gomes VJ, Romao-Veiga M, Ribeiro VR, Nunes PR, Romagnoli GG, et al. Silibinin downregulates the NF-κB pathway and NLRP1/NLRP3 inflammasomes in monocytes from pregnant women with preeclampsia. Molecules
2019; 24:1548doi: 10.3390/molecules24081548.
103. Park S, Shin J, Bae J, Han D, Park SR, Shin J, et al. Silibinin downregulates the NF-κB pathway and NLRP1/NLRP3 inflammasomes in monocytes from pregnant women with preeclampsia. Molecules
2019; 24:1548doi: 10.3390/molecules24081548.
104. American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care
2013; 36:S11–66. doi: 10.2337/dc13-S011.
105. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care
2004; 27:S88–90. doi: 10.2337/diacare.27.2007.s88.
106. Corrêa-Silva S, Alencar AP, Moreli JB, Borbely AU, de S, Lima L, Scavone C, et al. Hyperglycemia induces inflammatory mediators in the human chorionic villous. Cytokine
2018; 111:41–48. doi: 10.1016/j.cyto.2018.07.020.
107. Rehman K, Akash MS. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J Biomed Sci
2016; 23:87doi: 10.1186/s12929-016-0303-y.
108. Bacha F, Gidding SS. Cardiac Abnormalities in youth with obesity and type 2 diabetes. Curr Diab Rep
2016; 16:62doi: 10.1007/s11892-016-0750-6.
109. Berti C, Cetin I, Agostoni C, Desoye G, Devlieger R, Emmett PM, et al. Pregnancy and infants’ outcome: nutritional and metabolic implications. Crit Rev Food Sci Nutr
2016; 56:82–91. doi: 10.1080/10408398.2012.745477.
110. Zand H, Morshedzadeh N, Naghashian F. Signaling pathways linking inflammation to insulin resistance. Diabetes Metab Syndr
2017; 11:S307–S309. doi: 10.1016/j.dsx.2017.03.006.
111. Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A
2011; 108:15324–15329. doi: 10.1073/pnas.1100255108.
112. Ward R, Ergul A. Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes. Life Sci
2016; 159:97–103. doi: 10.1016/j.lfs.2016.02.043.
113. Głombik K, Trojan E, Kurek A, Budziszewska B, Basta-Kaim A. Inflammatory consequences of maternal diabetes on the offspring brain: a hippocampal organotypic culture study. Neurotox Res
2019; 36:357–375. doi: 10.1007/s12640-019-00070-6.
114. Zhang R, Zhang X, Xing B, Zhao J, Zhang P, Shi D, et al. Astragaloside IV attenuates gestational diabetes mellitus via targeting NLRP3 inflammasome in genetic mice. Reprod Biol Endocrinol
2019; 17:77doi: 10.1186/s12958-019-0522-7.
115. Negi M, Mulla MJ, Han CS, Abrahams VM. Allopurinol inhibits excess glucose-induced trophoblast IL-1β and ROS production. Reproduction
2020; 159:73–80. doi: 10.1530/REP-19-0422.
116. Ahn H, Kwon HM, Lee E, Kim PH, Jeung EB, Lee GS. Role of inflammasome regulation on immune modulators. J Biomed Res
2018; 32:401–410. doi: 10.7555/JBR.32.20170120.