title: Elevated postinjury thrombospondin 1-CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells.
abstract: 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.
authors.affiliation: Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Sanjukta
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Bankey
authors.affiliation: Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA carol_miller-graziano@urmc.rochester.edu.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Miller-Graziano
mesh_terms: D000328:Adult; D018949:Antigens, CD1 / Q000378:metabolism*; D051928:CD47 Antigen / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D050800:STAT6 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D019700:Thrombospondin 1 / Q000097:blood / Q000378:metabolism*; D014947:Wounds and Injuries / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D018949:Antigens, CD1; C419393:CD1a antigen; D051928:CD47 Antigen; D050800:STAT6 Transcription Factor; D019700:Thrombospondin 1; D015847:Interleukin-4
keywords: SHP-1 phosphatase; monocyte-derived DC; trauma patient