A role for CD47 in the development of experimental colitis mediated by SIRPα+CD103− dendritic cells

Abstract

Mesenteric lymph node (mLN) CD103 (αE 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 α (SIRPα) and promotes SIRPα+ myeloid cell migration. We first show that mucosal CD103− DCs selectively express SIRPα 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 SIRPα+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, SIRPα+CD103− DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPα+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 SIRPα+CD103− DC–mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPα+CD103− DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47–SIRPα axis as a potential therapeutic target for inflammatory bowel disease.

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

“…Notably, IL-17 injection also induced acute anemia and splenomegaly in Cd47 −/− mice. As reported previously, Cd47 −/− mice are resistant to low-dose DSSinduced colitis and are defective for IL-17 induction in vivo (34,35). This explains why low-dose DSS treatment does not induce anemia in Cd47 −/− mice, as anemia is secondary to the colitic condition and colitis-induced IL-17 (SI Appendix, Fig.…”

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…The pathogenicity of CD103 − DCs has been studied using only bone marrow-derived CD103 − DCs resulting from in vitro treatment with GM-CSF (11,12). Here, we show that CD103 − DCs directly isolated from MLNs express IL-6, IL-12, IL-23, and Opn and are pathogenic for colitis.…”

“…Instead, CD103 − DC function has been described mostly during chronic experimental colitis (10)(11)(12). These cells secrete IL-23, IL-6, and IL-12 (10)(11)(12), contributing to the development of T helper (Th) 17 and Th1 cells, and are highly inflammatory during CD4 + T-cell transfer colitis (12) and during 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis (11). MLN CD103 − DCs cultured in the presence of LPS, a Toll-like receptor (TLR) 4 agonist, or R848, a TLR7 agonist, express higher levels of TNF-α and IL-6 (7,12).…”

“…In fact, these cells secrete IL-23 and IL-12 even in the absence of TLR stimulation (10). Both MLN CD103 − and CD103 + DC subsets are present in acute colitis (11,13); however, their function, as well as their cytokine profile, during this phase of disease, reflecting colitis initiation, remains unknown.…”

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

“…NOD and NOR-derived Sirpa displayed extensive polymorphism resulting in 18-aa variations in the extracellular N-terminal Ig variable (IgV)-like domain responsible for binding the ligand CD47 (18). SIRPa signaling also control self-recognition functions of including clearance of red blood (19) and apoptotic cells by macrophages (20,21) and homeostasis of DC (22) as well as their ability to trigger Th cell responses (23,24). Given this sequence variation and its role in the immune response, we prioritized Sirpa as a candidate gene underlying the Idd13.2 locus.…”