The Role of Innate Immune IL-10 Receptor Signaling in Controlling Intestinal Immune Responses

Abstract

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine. Patients with deleterious mutations in either IL10 or its receptor (IL10R) develop severe inflammatory bowel disease (IBD) within the first months of life; similarly, Il10rb-/- mice develop spontaneous colitis. The precise mechanisms of IL-10R-dependent control of immune tolerance and intestinal mucosal homeostasis are not well defined. Here I demonstrate that IL-10R signaling in innate immune cells is critical for regulating mucosal homeostasis and prevention of colitis. Loss of IL-10R-dependent signaling caused wild-type CD4+ T cells to become colitogenic in a murine colitis transfer model. Moreover, My data indicate that IL-10R-dependent signals modulated the differentiation and function of bone-marrow-derived macrophages and intestinal macrophages into either pro-inflammatory macrophages or functionally competent anti-inflammatory macrophages in mice. Similarly, monocyte-derived macrophages from very early onset IBD patients harboring loss of function mutations in IL10RA and IL10RB genes also exhibited impaired differentiation and function of pro- and anti-inflammatory macrophages. These results define a unique and non-redundant role for IL-10R signaling in innate immune cell control of intestinal mucosal homeostasis in mice and humans.