IL-33–ILC2 axis in the female reproductive tract

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.