Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation
Ha-Na Lee, Linjie Tian, Nicolas Bouladoux, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, John E. Coligan, Konrad Krzewski
Ha-Na Lee, Linjie Tian, Nicolas Bouladoux, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, John E. Coligan, Konrad Krzewski
View: Text | PDF
Research Article Immunology Inflammation

Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation

Abstract

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.

Authors

Ha-Na Lee, Linjie Tian, Nicolas Bouladoux, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, John E. Coligan, Konrad Krzewski

×

Figure 6

Aggravation of colonic inflammation in the absence of CD300f.

Options: View larger image (or click on image) Download as PowerPoint
Aggravation of colonic inflammation in the absence of CD300f. DSS damage...
DSS damages intestinal epithelial cells and causes intestine barrier disruption, thereby allowing bacteria to penetrate intestinal barrier. To protect the host from microbial infection, neutrophils are recruited to such inflamed sites, kill the infiltrating bacteria, and undergo apoptosis. In normal conditions (CD300f WT, left), the apoptotic neutrophils are recognized and engulfed by phagocytes (mainly macrophages, Mϕ), which results in resolution of inflammation. However, under CD300f deficiency (CD300f KO, right), macrophages fail to efficiently engulf ACs, leading to accumulation and increased availability of ACs to CD300f-deficient DCs that inherently have increased efferocytic potential. Subsequently, AC-engulfing DCs produce TNF-α, which stimulates T cells (TC) and possibly other immune or nonimmune cells, to produce IFN-γ. Elevated levels of TNF-α and IFN-γ further damage the intestinal barrier, allowing for more bacteria to enter, resulting in prolonged recruitment of neutrophils to fight the microbial intrusion, which further contributes to sustained and elevated apoptosis and accumulation of ACs. In addition, chemoattractants and proinflammatory mediators released by activated neutrophils and mast cells (MC) result in further tissue damage and sustained recruitment of immune cells to the inflamed site, thus aggravating the intestinal inflammation. Eventually, a continuous proinflammatory feedback loop is generated, leading to chronic inflammation. Therefore, CD300f is important for preventing chronic inflammation in the gut by suppressing overactive DC inflammatory responses, and ensuring proper efferocytosis.