Interleukin-33-induced expression of PIBF1 by decidual B cells protects against preterm labor

Abstract

Preterm birth (PTB) is a leading cause of neonatal death worldwide1. Intrauterine and systemic infection and inflammation cause 30–40% of spontaneous preterm labor (PTL)2, which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL3,4, the functions of B cells in pregnancy are not well known5–8. We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell–deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell–deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the a-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL.

Molecular definition of group 1 innate lymphoid cells in the mouse uterus

“…In a cross talk similar to that of macrophages with peripheral NK cells, trNK cells may make IL-18 and stimulate cNK cells in the uterus, which in turn produce IFN-γ and stimulate trNK cells, which unexpectedly also both respond to and produce IL-1. IL-1 and IL-18 are part of the same family of cytokines, which also include the alarmin IL-33, and these are emerging as important factors in reproductive biology and pregnancy complications (Huang et al 2016; Bartemes et al 2017). IFN-γ is the key cytokine required for the reshaping of decidual vasculature in mice that leads to the formation of the placenta.…”

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition

“…This idea, in turn, suggests that preterm labor in the absence of infection might be the consequence of inappropriate exposure to epigenetic modifiers, either endogenous or environmental, acting potentially at any stage of gestation. Provocatively, idiopathic preterm labor has recently been associated with the choriodecidual upregulation of the human homologues of 2 H3K27me3 target genes, Tnfsf13b and Tslp, leading to B cell infiltration (36). Furthermore, the ability of GSK-J4 to prevent dinoprost-induced preterm labor without preventing luteolysis and consequently reduced plasma P4 suggests a link between decidual H3K27 demethylation and the functional P4 withdrawal also associated with idiopathic preterm labor.…”

Exploring the concentration‐dependent actions of interferon‐τ on bovine neutrophils to understand the process of implantation

“…42 Our findings indicate that neutrophils could also be a potential source of PIBF in cow uterus especially during early pregnancy. 42 This was further proved by our findings of lower expression of PIBF with higher concentrations of IFNT. 42 This was further proved by our findings of lower expression of PIBF with higher concentrations of IFNT.…”

“…The progesterone-inducible molecule PIBF1 carries out many effector functions of progesterone in pregnancy 41 and previous findings indicate that B cells are an important source of active PIBF1 in mouse gravid uterus. 42 Our findings indicate that neutrophils could also be a potential source of PIBF in cow uterus especially during early pregnancy. It was proved that PIBF administration suppresses proinflammatory mediators and inhibits neutrophil infiltration into the uterus with lower expression of CD11b.…”