Bandyopadhyay Gautam, Bandyopadhyay Sanjukta, Bankey Paul E, Miller-Graziano Carol L
Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Immunobiology and Stress Response Laboratory, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
J Leukoc Biol. 2014 Nov;96(5):797-807. doi: 10.1189/jlb.4MA0214-077R. Epub 2014 Jul 7.
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.
一部分患者会出现向炎症性树突状细胞（DC）分化及免疫抑制的功能失调单核细胞（MO）。髓样树突状细胞（MDDC）是一种新描述的DC亚群，在启动抗菌反应中起关键作用。已知内源性蛋白质会改变MO向MDDC的分化。特别是，创伤后升高的血小板反应蛋白-1（TSP-1），一种已知会影响MO功能的蛋白质，可引发MDDC分化缺陷。我们假设炎症性CD1a(+)MDDC的TSP-1紊乱分化会对免疫功能的激活产生负面影响，从而增加受伤后感染的风险。创伤后患者血浆和MO中TSP-1水平升高与两种不同的MDDC分化功能障碍相关：先前描述的CD1a(+)DC产量降低，以及无免疫活性的CD1a(+)MDDC的形成。患者功能失调DC（Dysf DC）的发展与感染并发症增加相关。TSP-1触发其抑制性受体CD47，激活抑制性磷酸酶SHP-1。患者Dysf DC的特征是pSHP-1增加、抗原加工减少和T细胞刺激受抑制。在对照MDDC分化过程中添加的TSP-1模拟物会降低CD1a(+)DC产量，但更重要的是，还会诱导有缺陷的CD1a(+)MDDC，重现患者的MDDC分化功能障碍。在对照MDDC分化过程中触发CD47会增加SHP-1激活，抑制白细胞介素-4诱导的信号转导和转录激活因子6（STAT-6）激活（对CD1a(+)MDDC分化至关重要）。在存在TSP-1模拟物的情况下，MDDC分化过程中抑制SHP-1可恢复磷酸化STAT-6水平和CD1a(+)MDDC的免疫原性。因此，受伤后升高的TSP-1可降低CD1a(+)DC产量，但更关键的是，还会诱导SHP-1过度活跃，通过抑制STAT-6使MDDC分化偏向有缺陷的CD1a(+)炎症性MDDC。
