Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency

Abstract

IL10 receptor (IL10R)-deficient mice develop spontaneous colitis and similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease (IBD). Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1 beta (IL1B). We demonstrated that innate immune production of IL1B mediates colitis in IL10R-deficient mice. Transfer of Il1r1−/− CD4+ T cells into Rag1−/−/Il10rb−/− mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1B through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide (LPS) and adenosine triphosphate stimulation of macrophages from Il10rb−/− mice or IL10R-deficient patients increased production of IL1B. Moreover, in human IL10R-deficient macrophages, LPS stimulation alone increased IL1B secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10-receptor deficient patients with severe and treatment-refractory infant-onset IBD with the IL1 receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4–7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4+ T cells. Agents that block IL1 signaling might be used to treat patients with IBD resulting from IL10R deficiency.