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

Autor: Bandyopadhyay G; Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Bandyopadhyay S; Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Bankey PE; Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Miller-Graziano CL; Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA carol_miller-graziano@urmc.rochester.edu.
Jazyk: angličtina
Zdroj: Journal of leukocyte biology [J Leukoc Biol] 2014 Nov; Vol. 96 (5), pp. 797-807. Date of Electronic Publication: 2014 Jul 07.
DOI: 10.1189/jlb.4MA0214-077R
Abstrakt: 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.
(© 2014 Society for Leukocyte Biology.)
Databáze: MEDLINE
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