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
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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

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Figure 4

PS-mediated engulfment of ACs by CD300f-deficient DCs induces their TNF-α production, and stimulates IFN-γ secretion by T cells.

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PS-mediated engulfment of ACs by CD300f-deficient DCs induces their TNF-...
(A) The presence of ACs in colons was assessed by TUNEL staining. The images show representative immunofluorescence staining for TUNEL (red) in colon sections from CD300f+/+ and CD300f–/– mice. Nuclei were visualized with DAPI (blue). Scale bars: 50 μm. The graphs show the quantification of TUNEL+ cells per field of view (3 fields per colon section). (B) CD300f+/+ or CD300f–/– BMDCs were coincubated with pHrodo-labeled apoptotic thymocytes for 30 minutes, followed by confocal microscopy analysis. The images (top) show representative images of BMDCs with engulfed ACs (white); scale bars: 10 μm. The graph (bottom) shows the quantification of AC engulfment by BMDCs. (C–E) BMDCs or BMMϕ from CD300f+/+ or CD300f–/– mice were coincubated with apoptotic thymocytes in the absence (C and E) or the presence of PBS, PS:PC liposomes, or PC:PC liposomes (D) for 30 minutes, followed by incubation in a fresh medium for 48 hours. The cell culture media were collected and used to analyze the levels of the indicated cytokines (C and D) or to culture splenic T cells for 48 hours in the presence or absence of anti–TNF-α antibodies (E). To calculate the concentration of IFN-γ released from T cells, the amount of cytokines present in the conditioned media was subtracted from the final values. The media from T cells cultured for 48 hours in the presence of TNF-α (200 ng/ml) were used as a positive control (E). Data are expressed as means + SEM (n = 15, each group in A; n = 50 cells analyzed in 3 independent experiments in B; n = 3 in C–E). Two-tailed paired Student’s t test was used to determine statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001).