Inflammasome signaling in human placental trophoblasts regulates immune defense against Listeria monocytogenes infection

Abstract

The human placenta is a dynamic organ that modulates physiological adaptations to pregnancy. To define the immunological signature of the human placenta, we performed unbiased profiling of secreted immune factors from human chorionic villi isolated from placentas at mid and late stages of pregnancy. We show that placental trophoblasts constitutively secrete the inflammasome-associated cytokines IL-1β and IL-18, which is blocked by NLRP3 inflammasome inhibitors and occurs without detectable gasdermin D cleavage. We further show that placenta-derived IL-1β primes monocytes for inflammasome induction to protect against Listeria monocytogenes infection. Last, we show that the human placenta responds to L. monocytogenes infection through additional inflammasome activation and that inhibition of this pathway sensitizes villi to infection. Our results thus identify the inflammasome as an important mechanism by which the human placenta regulates systemic and local immunity during pregnancy to defend against L. monocytogenes infection.

Placental inflammasome signaling: Protection for mother and baby

“…One well-established function of IL-1β in other settings is its capacity to "prime" cells for heightened responses to other stimuli, such as inflammasome-activating factors. Megli and colleagues showed that placental IL-1β production during midgestation is associated with increased IL-1β levels in serum and up-regulated expression of caspase-1 and IL-1β in circulating monocytes (Megli et al, 2020). Conditioned media from chorionic villous explants from pregnant women similarly primed the monocytes of nonpregnant women for up-regulated IL-1β, caspase-1, and NLRP3 expression.…”

“…SYNs are reported to recognize pathogens via Toll-like receptors and RIG-I-like receptors (Koga and Mor, 2008), but their capacity to sense microbes or cell stress via the inflammasome was unknown. To investigate the mechanism underpinning cytokine production by chorionic villi, Megli et al (2020) performed detailed RNA sequencing analyses of trophoblasts isolated from chorionic villi. Indeed, midgestation trophoblasts expressed high levels of inflammasome-associated molecules such as caspase-1, NLRP3, IL-1β, and IL-18.…”

“…L. monocytogenes infection is a major concern during pregnancy, as this bacterium is vertically transmitted along the maternal-fetal barrier, where it can cause fetal infection and premature death. With the hypothesis that placental IL-1β poises circulating maternal monocytes for heightened antimicrobial responses to microbes that may endanger the fetus, Megli et al (2020) assessed the impact of priming on monocyte defense against L. monocytogenes. THP-1 monocytes primed with chorionic villous-derived conditioned media were indeed less susceptible to L. monocytogenes.…”

“…that trophoblast inflammasome signaling contributes to antimicrobial defense, Megli et al (2020) isolated chorionic villous explants from women in their second trimester of pregnancy. Explant infection with L. monocytogenes triggered strong IL-1β and IL-18 production.…”

“…Megli and co-workers sought to determine whether trophoblasts protect the fetus during pregnancy (Megli et al, 2020). The authors used multianalyte Luminex methods to profile secreted factors from chorionic villi isolated from pregnant women.…”