Elevated postinjury thrombospondin 1–CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells

Post‐injury differentiation of dysfunctional CD1a+monocytederived dendritic cells can result from elevated thrombospondin‐1, triggering CD47, and increasing inhibitory SHP‐1 activation and immunodepression. A subset of Pts develops dysfunctional MO to inflammatory DC differentiation and immunosuppression. MDDC, a newly described DC subset, is pivotal in initiating antibacterial responses. Endogenous proteins are known to alter MO to MDDC differentiation. In particular, trauma‐elevated TSP‐1, a protein that is known to affect MO functions, could trigger MDDC differentiation defects. We hypothesized that TSP‐1‐deranged differentiation of inflammatory CD1a+MDDC would negatively alter activation of immune functions, thereby increasing the risk of postinjury infections. Post‐trauma increased TSP‐1 levels in patients' plasma and MO correlated with two distinct MDDC differentiation dysfunctions: the previously described decreased CD1a+DC yields but also, development of an immunoincompetent CD1a+MDDC. The Pts' development of Dysf DC correlated to increased infectious complications. TSP‐1 triggered its inhibitory receptor, CD47, activating an inhibitory phosphatase, SHP‐1. Increased pSHP‐1, decreased antigen processing, and depressed T cell stimulation characterized Pt Dysf DC. TSP‐1 mimics added during Cnt MDDC differentiation depressed CD1a+DC yields but more importantly, also induced defective CD1a+MDDC, reproducing Pts' MDDC differentiation dysfunctions. CD47 triggering during Cnt MDDC differentiation increased SHP‐1 activation, inhibiting IL‐4‐induced STAT‐6 activation (critical for CD1a+MDDC differentiation). SHP‐1 inhibition during MDDC differentiation in the presence of TSP‐1 mimics restored pSTAT‐6 levels and CD1a+MDDC immunogenicity. Thus, postinjury‐elevated TSP‐1 can decrease CD1a+DC yields but more critically, also induces SHP‐1 hyperactivity, deviating MDDC differentiation to defective CD1a+inflammatory MDDCs by inhibiting STAT‐6.