IL-33–ILC2 axis in the female reproductive tract

IL-33, an alarmin or danger signal that is normally released by damaged or necrotic cells, has emerged as a pleiotropic cytokine that can regulate physiological and pathological processes associated with chronic inflammation, homeostasis, infection, and cancer progression. IL-33 is considered to be a 'double-edged sword' cytokine that not only perpetuates type 2 inflammation (anti-inflammatory inflammation) but can also stimulate type 1, proinflammatory, antitumor, and antiviral responses In the female reproductive tract, both IL-33 and its receptor [suppressor of tumorgenicity 2 (ST2)] are present, but their expression varies across the menstrual or estrous cycle. Although the exact mechanism is not known, the IL-33–ST2/ group 2 innate lymphoid cell (ILC2) axis seems to contribute functionally not only to healthy pregnancy including embryo implantation and placental development but also to reproductive infections, pathologies, and malignancies. IL-33 is a member of the IL-1 family and was first identified as an alarmin that acts at mucosal barrier sites. However, IL-33 is now understood to be a pleiotropic cytokine that acts on a variety of immune and non-immune cell types to promote type 2 T helper cell (TH2) inflammation as well as to regulate and suppress homeostatic processes. Of particular interest are group 2 innate lymphoid cells (ILC2s) which are activated by IL-33 and promote many IL-33-specific effects. Considerable investigation has surrounded the integral role of IL-33 and ILC2s in driving inflammation in asthma, allergy, atopic dermatitis, fibrotic diseases, microbial interactions, and more. However, IL-33 and ILC2s have also emerged as key components of a healthy pregnancy and fertility; when dysregulated, they can drastically drive female reproductive pathologies. We first summarize the presence of both IL-33 and ILC2s in the female reproductive tract (FRT) and in healthy pregnancy. We then provide insights into how IL-33 and ILC2s drive female reproductive pathologies and how this axis could be a potential therapeutic target in reproductive disorders including preterm birth, pre-eclampsia, recurrent spontaneous abortion, and endometriosis. IL-33 is a member of the IL-1 family and was first identified as an alarmin that acts at mucosal barrier sites. However, IL-33 is now understood to be a pleiotropic cytokine that acts on a variety of immune and non-immune cell types to promote type 2 T helper cell (TH2) inflammation as well as to regulate and suppress homeostatic processes. Of particular interest are group 2 innate lymphoid cells (ILC2s) which are activated by IL-33 and promote many IL-33-specific effects. Considerable investigation has surrounded the integral role of IL-33 and ILC2s in driving inflammation in asthma, allergy, atopic dermatitis, fibrotic diseases, microbial interactions, and more. However, IL-33 and ILC2s have also emerged as key components of a healthy pregnancy and fertility; when dysregulated, they can drastically drive female reproductive pathologies. We first summarize the presence of both IL-33 and ILC2s in the female reproductive tract (FRT) and in healthy pregnancy. We then provide insights into how IL-33 and ILC2s drive female reproductive pathologies and how this axis could be a potential therapeutic target in reproductive disorders including preterm birth, pre-eclampsia, recurrent spontaneous abortion, and endometriosis. a specialized cytokine that induces leukocyte chemotaxis. the diverse population of microorganisms that are found at barrier and mucosal sites. the modified layer of the endometrium that becomes the maternal part of the placenta. a specialized NK cell found in the decidua during pregnancy that is devoid of cytotoxicity but releases cytokines and chemokines that are crucial for placentation. a chronic inflammatory gynecological disease characterized by the growth of endometrial tissue lesions in extrauterine locations including the ovary, peritoneal wall, and sigmoid colon. the repetitive reproductive cycle of non-primate mammals. The process is divided into four stages: proestrus, estrus, metestrus, and diestrus, and is distinct from the menstrual cycle in many ways; one being that the endometrium is reabsorbed and not shed. a specialized, differentiated trophoblast (fetal portion of the placenta) that migrates and invades into the maternal decidua. a pathological wound-healing process resulting in the accumulation of dense fibrous connective tissue, typically at the site of an injury or damage. the process of ovarian follicle maturation and atresia. a term used to describe a specific date during gestation. a parasitic worm typically characterized by elongated, flat, or round bodies. unnecessary and exaggerated immune reaction in response to exposure to a particular antigen or allergen in inflammatory conditions including allergies and autoimmunity. a subset of lymphocytes that are categorized as the analogous, innate counterpart of T cells. composed of the vagina and ectocervix, the lower FRT is lined with stratified squamous non-keratinized epithelium. a term used to describe both the maternally derived decidua and the fetus-derived placenta. the cyclical reproductive cycle occurring in primates including humans. The process is divided into four stages – menstruation, the follicular phase, ovulation, and the luteal phase. a specialized structure containing small, agranulate uterine NK cells. It develops in the murine uterine wall smooth muscle at around GD8.5 and surrounds the arteries and veins supplying the implantation site. a complex pregnancy pathology categorized by hypertension after 20 weeks of gestation. the onset of labor and birth before 37 weeks of gestation in humans. the pathological condition of three or more consecutive spontaneous abortions. bacterial, viral, or other infections that are acquired through sexual contact. is composed of the endocervical canal, uterus, and fallopian tubes, and is lined by a single-layer columnar epithelium.