NLRP3 mediates trophoblastic inflammasome activation and protects against Listeria monocytogenes infection during pregnancy

Background: Intrauterine Listeria monocytogenes (L. monocytogenes) infections pose a major threat during pregnancy via affecting placental immune responses. However, the underlying mechanisms of placental defense against this pathogen remain ill-defined. Therefore, this study aims to investigate the function and the mechanism of inflammasomes on against L. monocytogenes infection during pregnancy.Methods: A listeriosis murine model and cell culture system was used to investigate the role of trophoblastic nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) in orchestrating innate immune responses to L. monocytogenes infection. Caspase-1 activity was determined using a caspase-1 activity colorimetric kit. NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) in placental tissue was detected by immunohistochemistry. NLRP3 in HTR-8/SVneo cells was also detected by immunofluorescence. The expression of interleukin 113 (IL-113), NLRP3, ASC, and caspase-1 was detected by Western blot. We characterized the NLRP3 inflammasome in trophoblast cells according to whether L. monocytogenes infection increased the activation of caspase-1 and the release of IL-113. For human or mouse IL-113 in the culture supernatants and mouse tissue lysates were analyzed using ELISA Kits.Results: Trophoblast cells constitutively expressed the components of the NLRP3 inflammasome. In vitro, L. monocytogenes triggers NLRP3 inflammasome activation in trophoblast cells by inducing caspase-1 activation, increasing the NLRP3 protein levels, IL-113 maturation and secretion in HTR-8/SVneo cells. In vivo, L. monocytogenes induces fetal resorption and IL-113 processing in pregnant mice. In addition, NLRP3-deficient mice were more prone to fetal loss than their wild-type counterparts following infection with L. monocytogenes at a lower infective doseConclusions: We conclude that trophoblast cells respond to L. monocytogenes infection through the NLRP3 receptor, resulting in inflammasome activation and IL-113 production, which prevents listeriosis during pregnancy.

Automated summary

This study found that trophoblast cells express the NLRP3 inflammasome and can activate inflammasome, promote the production and release of IL-113 in response to L. monocytogenes infection. In mouse experiments, L. monocytogenes infection resulted in fetal resorption and IL-113 processing. Additionally, mice lacking NLRP3 were more susceptible to miscarriage at a lower infective dose compared to the wild-type group.