IL-33 Is Required for Disposal of Unnecessary Cells during Ovarian Atresia through Regulation of Autophagy and Macrophage Migration

Abstract

Physiological processes such as ovarian follicle atresia generate large amounts of unnecessary cells or tissue detritus, which needs to be disposed of rapidly. Interleukin33 (IL33) is a member of the IL1 cytokine gene family. Consecutive expression of IL33 in a wide range of tissues has hinted at its role beyond immune defense. We have previously reported a close correlation between IL33 expression patterns and ovarian atresia. Here, we demonstrated that IL33 is required for disposal of degenerative tissue during ovarian atresia using Il33−/− mice. Deletion of the Il33 gene impaired normal disposal of atretic follicles, resulting in massive accumulations of tissue wastes abundant with aging-related catabolic wastes such as lipofuscin. Accumulation of tissue wastes in Il33−/− mice, in turn, accelerated ovarian aging and functional decline. Thus, their reproductive lifespan was shortened to 2/3 of that for Il33+/− littermates. IL33 orchestrated disposal mechanism through regulation of autophagy in degenerating tissues and macrophage migration into the tissues. Our study provided direct evidence supporting an expanded role of IL33 in tissue integrity and aging through regulating disposal of unnecessary tissues or cells.

The physiological roles of autophagy in the mammalian life cycle

“…During ovarian development, KIT proto‐oncogene receptor tyrosine kinase (KIT) promotes autophagy by activation of the PI3K–AKT serine/threonine kinase (AKT)–mTOR pathway, and inhibition of PI3K–AKT–mTOR results in dramatically decreased generation of germ cells (Adhikari et al ., ; Gawriluk et al ., ). Further mechanistic studies have shown that IL‐33, a member of the IL‐1 cytokine family, is responsible for the rapid clearance of cellular waste generated during follicular atresia by inducing autophagy (Wu et al ., ). Thus, autophagy has been proposed to be essential for maintaining the pool of dormant female germ cells.…”

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

“…IL-33 was reported in placental macrophages and shown to promote the growth of trophoblasts (Fock et al, 2013). Ovarian IL-33 and ST2 increase with ovulation (Carlock et al, 2014), where IL-33 is expressed by endothelial cells surrounding developing follicles (Wu et al, 2015). IL-33 is required for recruitment of macrophages to mediate ovarian atresia post-ovulation, and IL-33-deficient mice show a 33% reduction in reproductive lifespan (Wu et al, 2015).…”

“…Ovarian IL-33 and ST2 increase with ovulation (Carlock et al, 2014), where IL-33 is expressed by endothelial cells surrounding developing follicles (Wu et al, 2015). IL-33 is required for recruitment of macrophages to mediate ovarian atresia post-ovulation, and IL-33-deficient mice show a 33% reduction in reproductive lifespan (Wu et al, 2015). These findings suggest IL-33 may promote the physiologic clearance of atretic ovarian follicles and possibly promote uterine and placental remodeling in the course of the estrous cycle and pregnancy.…”

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…Macrophage-derived signals are also important for vessel integrity of the antral follicle and corpus luteum, since whole body ablation of macrophages results in hemorrhage limitedly to the ovaries and not other tissues (Care et al, 2013;Turner et al, 2011). Apoptosis of granulosa and luteal cells is triggered by inflammatory mediators, including TNFα, while an increased macrophage number in the atretic follicle and corpus albicans has been associated with tissue regression and removal through the release of catabolic mediators and phagocytosis (Carlock et al, Shirasuna et al, 2013;Stocco et al, 2007;Wu et al, 2015).…”