Proinflammatory cytokine overproduction and excessive cell death, coupled with impaired clearance of apoptotic cells, have been implicated as causes of failure to resolve gut inflammation in inflammatory bowel diseases. Here we have found that dendritic cells expressing the apoptotic cell–recognizing receptor CD300f play a crucial role in regulating gut inflammatory responses in a murine model of colonic inflammation. CD300f-deficient mice failed to resolve dextran sulfate sodium–induced colonic inflammation as a result of defects in dendritic cell function that were associated with abnormal accumulation of apoptotic cells in the gut. CD300f-deficient dendritic cells displayed hyperactive phagocytosis of apoptotic cells, which stimulated excessive TNF-α secretion predominantly from dendritic cells. This, in turn, induced secondary IFN-γ overproduction by colonic T cells, leading to prolonged gut inflammation. Our data highlight a previously unappreciated role for dendritic cells in controlling gut homeostasis and show that CD300f-dependent regulation of apoptotic cell uptake is essential for suppressing overactive dendritic cell–mediated inflammatory responses, thereby controlling the development of chronic gut inflammation.
Ha-Na Lee, Linjie Tian, Nicolas Bouladoux, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, John E. Coligan, Konrad Krzewski
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