A role for CD47 in the development of experimental colitis mediated by SIRPalpha+CD103- dendritic cells.
Mesenteric lymph node (mLN) CD103 (alphaE integrin)(+) dendritic cells (DCs) induce regulatory T cells and gut tolerance. However, the function of intestinal CD103(-) DCs remains to be clarified. CD47 is the ligand of signal regulatory protein alpha (SIRPalpha) and promotes SIRPalpha(+) myeloid cell migration. We first show that mucosal CD103(-) DCs selectively express SIRPalpha and that their frequency was augmented in the lamina propria and mLNs of mice that developed Th17-biased colitis in response to trinitrobenzene sulfonic acid. In contrast, the percentage of SIRPalpha(+)CD103(-) DCs and Th17 responses were decreased in CD47-deficient (CD47 knockout [KO]) mice, which remained protected from colitis. We next demonstrate that transferring wild-type (WT), but not CD47 KO, SIRPalpha(+)CD103(-) DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPalpha(+)CD103(-) DCs for efficient trafficking to mLNs in vivo, whereas it was dispensable on both DCs and T cells for Th17 polarization in vitro. Finally, administration of a CD47-Fc molecule resulted in reduced SIRPalpha(+)CD103(-) DC-mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPalpha(+)CD103(-) DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47-SIRPalpha axis as a potential therapeutic target for inflammatory bowel disease.
Fortin
Genevieve
G
Research Institute of McGill University Health Centre, McGill University, Montreal H3H 2R9, Canada.
Raymond
Marianne
M
Van
Vu Quang
VQ
Rubio
Manuel
M
Gautier
Patrick
P
Sarfati
Marika
M
Franchimont
Denis
D
D000818:Animals; D015703:Antigens, CD; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D039001:Integrin alpha Chains / Q000172:deficiency; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D019282:Wasting Syndrome / Q000209:etiology / Q000276:immunology*
D015703:Antigens, CD; D051928:CD47 Antigen; D039001:Integrin alpha Chains; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C091367:alpha E integrins; D014302:Trinitrobenzenesulfonic Acid
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