Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes†

Gomez‐Lopez, Nardhy; Romero, Roberto; Garcia‐Flores, Valeria; Leng, Yaozhu; Miller, Derek; Hassan, Sonia S.; Hsu, Chaur‐Dong; Panaitescu, Bogdan

doi:10.1093/biolre/ioy264

Cited by 85 publications

(82 citation statements)

References 144 publications

(177 reference statements)

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“…Consistent with the human findings, the depletion of Tregs during the third week of pregnancy induced preterm birth that was restored upon the adoptive transfer of such cells. The rates of preterm birth resulting from the depletion of Tregs were modest compared to animal models of systemic and local acute inflammation-induced preterm birth ( St Louis et al, 2016 ; Gomez-Lopez et al, 2016a , 2016b , 2018 , 2019 ; Garcia-Flores et al, 2018 ). However, this is consistent with the current belief that different subsets of preterm labor and birth are mediated through different mechanisms ( Romero et al, 2014a ).…”

Section: Discussionmentioning

confidence: 88%

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

et al. 2020

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SUMMARY Regulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive transfer of such cells. Treg depletion does not alter obstetrical parameters in the mother, yet it increases susceptibility to endotoxin-induced preterm birth. The mechanisms whereby depletion of Tregs induces adverse perinatal outcomes involve tissue-specific immune responses and mild systemic maternal inflammation, together with dysregulation of developmental and cellular processes in the placenta, in the absence of intra-amniotic inflammation. These findings provide mechanistic evidence supporting a role for Tregs in the pathophysiology of idiopathic preterm labor/birth and adverse neonatal outcomes.

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Section: Discussionmentioning

confidence: 88%

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

et al. 2020

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“…This intraamniotic inflammatory response can result in deleterious effects on the offspring [27,28,[44][45][46][47][48][49]. Therefore, the elucidation of the mechanisms involved in intra-amniotic inflammation leading to preterm birth is critical for the development of novel treatment strategies to reduce adverse neonatal outcomes [50,51].…”

Section: Introductionmentioning

confidence: 99%

Intra-amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome†

Faro

Romero²,

Schwenkel

et al. 2018

Biology of Reproduction

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Intra-amniotic inflammation is strongly associated with spontaneous preterm labor and birth, the leading cause of perinatal mortality and morbidity worldwide. Previous studies have suggested a role for the NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome in the mechanisms that lead to preterm labor and birth. However, a causal link between the NLRP3 inflammasome and preterm labor/birth induced by intra-amniotic inflammation has not been established. Herein, using an animal model of lipopolysaccharide-induced intra-amniotic inflammation (IAI), we demonstrated that there was priming of the NLRP3 inflammasome (1) at the transcriptional level, indicated by enhanced mRNA expression of inflammasome-related genes (Nlrp3, Casp1, Il1b); and (2) at the protein level, indicated by greater protein concentrations of NLRP3, in both the fetal membranes and decidua basalis prior to preterm birth. Additionally, we showed that there was canonical activation of the NLRP3 inflammasome in the fetal membranes, but not in the decidua basalis, prior to IAI-induced preterm birth as evidenced by increased protein levels of active caspase-1. Protein concentrations of released IL1β were also increased in both the fetal membranes and decidua basalis, as well as in the amniotic fluid, prior to IAI-induced preterm birth. Finally, using the specific NLRP3 inhibitor, MCC950, we showed that in vivo inhibition of the NLRP3 inflammasome reduced IAI-induced preterm birth and neonatal mortality. Collectively, these results provide a causal link between NLRP3 inflammasome activation and spontaneous preterm labor and birth in the context of intra-amniotic inflammation. We also showed that, by targeting the NLRP3 inflammasome, adverse pregnancy and neonatal outcomes can be significantly reduced.

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“…The mechanisms leading to sterile intra-amniotic inflammation involve the activation of the NLRP3 inflammasome in the chorioamniotic membranes [81,82,85]. Indeed, animal experimentation has shown that alarmins (molecules that trigger sterile inflammation [225][226][227]) are capable of activating the NLRP3 inflammasome in the fetal membranes [228]. Importantly, these studies have generated promising data showing that, by tackling the activation of the NLRP3 inflammasome, sterile intra-amniotic inflammation can be treated and preterm birth prevented.…”

Section: Microbial Burden Correlated With Intra-amniotic Inflammasomementioning

confidence: 99%

Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes

Theis

Romero

Motomura

et al. 2020

Journal of Perinatal Medicine

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Background Intra-amniotic inflammation, which is associated with adverse pregnancy outcomes, can occur in the presence or absence of detectable microorganisms, and involves activation of the inflammasome. Intra-amniotic inflammasome activation has been reported in clinical chorioamnionitis at term and preterm labor with intact membranes, but it has not yet been investigated in women with preterm prelabor rupture of membranes (preterm PROM) in the presence/absence of detectable microorganisms. The aim of this study was to determine whether, among women with preterm PROM, there is an association between detectable microorganisms in amniotic fluid and intra-amniotic inflammation, and whether intra-amniotic inflammasome activation correlates with microbial burden. Methods Amniotic fluids from 59 cases of preterm PROM were examined for the presence/absence of microorganisms through culture and 16S ribosomal RNA (rRNA) gene quantitative real-time polymerase chain reaction (qPCR), and concentrations of interleukin-6 (IL-6) and ASC [apoptosis-associated spec-like protein containing a caspase recruitment domain (CARD)], an indicator of inflammasome activation, were determined. Results qPCR identified more microbe-positive amniotic fluids than culture. Greater than 50% of patients with a negative culture and high IL-6 concentration in amniotic fluid yielded a positive qPCR signal. ASC concentrations were greatest in patients with high qPCR signals and elevated IL-6 concentrations in amniotic fluid (i.e. intra-amniotic infection). ASC concentrations tended to increase in patients without detectable microorganisms but yet with elevated IL-6 concentrations (i.e. sterile intra-amniotic inflammation) compared to those without intra-amniotic inflammation. Conclusion qPCR is a valuable complement to microbiological culture for the detection of microorganisms in the amniotic cavity in women with preterm PROM, and microbial burden is associated with the severity of intra-amniotic inflammatory response, including inflammasome activation.

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Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes†

Cited by 85 publications

References 144 publications

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

Intra-amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome†

Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes

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