CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation and colitogenic TH17 responses in mice

Abstract

The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1 million people in the United States. Uncontrolled APC reactivity toward commensal bacteria is implicated in the pathogenesis of the disease. A number of distinct APC populations exist in the intestinal lamina propria (LP), but their relative contributions to inflammation remain unclear. Here, we demonstrate important roles for the chemokine receptor CX3CR1 in maintaining LP macrophage populations, preventing translocation of commensal bacteria to mesenteric lymph nodes (mLNs), and limiting colitogenic Th17 responses. CX3CR1 was expressed in resident LP macrophages but not DCs. LP macrophages were decreased in two strains of CX3CR1‐knockout mice and in mice deficient in CX3CL1. All these knockout strains displayed markedly increased translocation of commensal bacteria to mLNs. Additionally, the severity of DSS‐induced colitis was dramatically enhanced in the knockout mice as compared with controls. Disease severity could be limited by either administration of neutralizing IL‐17A antibodies or transfer of CX3CR1‐sufficient macrophages. Our data thus suggest key roles for the CX3CR1/CX3CL1 axis in the intestinal mucosa; further clarification of CX3CR1 function will likely direct efforts toward therapeutic intervention for mucosal inflammatory disorders.