In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 96, No. 5 ( 2014-07-07), p. 797-807
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.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
DOI:
10.1189/jlb.4MA0214-077R
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2014
detail.hit.zdb_id:
2026833-6
SSG:
12
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