The IL-33/ILC2 axis in parturition

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Parturition in humans is thought to be a uterus-intrinsic process since it occurs without a decline in the serum progesterone (P4) levels. However, this process remains mysterious: not only is the nature of the “clock” that times gestation length completely obscure, but little is known about the sequence of cellular and molecular events initiated at term gestation that ultimately culminate in uterine contraction. Unfortunately, uterus-intrinsic parturition pathways have not been dissected mechanistically, as studies performed in mice and rats have instead addressed these species' superimposed, endocrine-mediated parturition pathway that involves shutdown of P4 synthesis by the ovary (i.e. luteolysis). This leaves a fundamental gap in knowledge with profound negative implications for human health since it precludes attempts to develop rational therapies for preterm birth, a major cause of neonatal morbidity and mortality. Here, we address how parturition is controlled by the IL-1 cytokine family member IL-33 and its key target cell type, the group 2 innate lymphoid cell (ILC2). Strikingly, we have found that IL-33 deficient mice as well as Rag2-/- Il2rg-/- mice lacking all lymphocytes including ILC2s are unable to initiate parturition when they are supplemented with exogenous P4 to circumvent the impact of luteolysis. In contrast, P4-treated Rag2-/- mice lacking T and B cells but retaining innate lymphoid cells undergo parturition with comparable timing to B6 controls. We have also found that ILC2s expand in the myometrium with advancing gestation in an IL-33-dependent fashion, and that IL-33 is produced within the late gestation uterus primarily by its stromal constituents. Together, these results suggest that ILC2 activation within the myometrium, initiated in late gestation by IL-33 produced by uterine stromal cells, is a key component of the uterus-intrinsic pathway of parturition in mice. We propose to substantiate this hypothesis with the ultimate goal of understanding how the IL-33/ILC2 axis might be involved in normal human parturition and the pathophysiology of preterm birth. The proposal has three Specific Aims. Aim 1 will use mice with various uterus- and cell type-specific defects in the IL-33/ST2 axis to delineate the exact cellular and temporal requirements for IL-33 and ILC2s in parturition. Aim 2 will then identify the effector mechanisms through which IL-33 promotes parturition by first evaluating known parturition components and potential candidate pathways suggested by our preliminary data, and then by taking unbiased approaches to reveal additional downstream candidates. Aim 3 will then evaluate whether the IL-33/ILC2 axis is involved in the pathophysiology of preterm parturition in mice and, by analyzing archived hysterectomy specimens, in term and preterm parturition in humans. Together, we expect these studies to provide clear cellular and molecular definition to a key, uterus-intrinsic regulatory circuit that drives parturition in mice. As such, they might open up new avenues for dissecting the mechanisms of human parturition and for determining how such mechanisms are dysregulated in disorders of human pregnancy.