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

被引：81

作者：

Gomez-Lopez, Nardhy ^{[1
,2
,3
,4
]}

Romero, Roberto ^{[1
,2
,5
,6
,7
]}

Garcia-Flores, Valeria ^{[1
,2
,3
]}

Leng, Yaozhu ^{[1
,2
,3
]}

Miller, Derek ^{[1
,2
,3
]}

Hassan, Sonia S. ^{[1
,2
,3
,8
]}

Hsu, Chaur-Dong ^{[3
,8
]}

Panaitescu, Bogdan ^{[1
,2
,3
]}

机构：

[1] US Dept HHS, Perinatol Res Branch, Div Obstet & Maternal Fetal Med,NIH, Div Intramural Res,Eunice Kennedy Shriver Natl In, Bethesda, MD USA

[2] US Dept HHS, Perinatol Res Branch, Div Obstet & Maternal Fetal Med,NIH, Div Intramural Res,Eunice Kennedy Shriver Natl In, Detroit, MI USA

[3] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA

[4] Wayne State Univ, Sch Med, Dept Immunol Microbiol & Biochem, Detroit, MI USA

[5] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA

[6] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA

[7] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA

[8] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA

来源：

BIOLOGY OF REPRODUCTION | 2019年 / 100卷 / 05期

基金：

美国国家卫生研究院;

关键词：

acute chorioamnionitis; alarmins; amniotic fluid; caspase-1; cytokines; damage-associated molecular patterns; danger signals; funisitis; interleukin-1; beta; mice; inhibitor; S100B; WHITE-MATTER LESIONS; AMNIOTIC INFECTION SYNDROME; UMBILICAL-CORD PLASMA; GAMMA-INDUCING FACTOR; CLINICAL CHORIOAMNIONITIS; INTRAUTERINE INFECTION; BRONCHOPULMONARY DYSPLASIA; VAGINAL PROGESTERONE; MICROBIAL INVASION; SPONTANEOUS LABOR;

D O I：

10.1093/biolre/ioy264

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Sterile intra-amniotic inflammation is commonly observed in patients with spontaneous preterm labor, a syndrome that commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. However, the mechanisms leading to sterile intra-amniotic inflammation are poorly understood and no treatment exists for this clinical condition. Herein, we investigated whether the alarmin S100B could induce sterile intra-amniotic inflammation by activating the NLRP3 inflammasome, and whether the inhibition of this pathway could prevent preterm labor/birth and adverse neonatal outcomes. We found that the ultrasound-guided intra-amniotic administration of S100B induced a 50% rate of preterm labor/birth and a high rate of neonatal mortality (59.7%) without altering the fetal and placental weights. Using a multiplex cytokine array and immunoblotting, we reported that S100B caused a proinflammatory response in the amniotic cavity and induced the activation of the NLRP3 inflammasome in the fetal membranes, indicated by the upregulation of the NLRP3 protein and increased release of active caspase-1 and mature IL-1 beta. Inhibition of the NLRP3 inflammasome via the specific inhibitor MCC950 prevented preterm labor/birth by 35.7% and reduced neonatal mortality by 26.7%. Yet, inhibition of the NLRP3 inflammasome at term did not drastically obstruct the physiological process of parturition. In conclusion, the data presented herein indicate that the alarmin S100B can induce sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes by activating the NLRP3 inflammasome, which can be prevented by inhibiting such a pathway. These findings provide evidence that sterile intra-amniotic inflammation could be treated by targeting the NLRP3 inflammasome. Intra-amniotic administration of the alarmin S100B, at clinically relevant concentrations, induces preterm labor/birth and adverse neonatal outcomes by activating the NLRP3 inflammasome, which can be prevented by targeting this pathway.

引用

页码：1306 / 1318

页数：13

共 143 条

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