Thrombospondin-1 activation of signal-regulatory protein-? stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

ABSTRACT: Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-? (SIRP-?) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-? in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondin-1 and SIRP-? on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-?. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-? and downstream activation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47(phox) (an organizer subunit for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1/2) and increased production of superoxide, both of which were abrogated by knockdown or antibody blockade of SIRP-?. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-?-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-? signaling axis and was associated with increased superoxide production and cell death. A SIRP-? antibody that blocks thrombospondin-1 activation of SIRP-? mitigated the effects of renal IRI, increasing blood flow, suppressing production of reactive oxygen species, and preserving cellular architecture. A role for CD47 in SIRP-? activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-? on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.

SUBMITTER: Yao M 

PROVIDER: S-EPMC4033366 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature