Ischemia reperfusion injury (IRI) remains a source of organ transplant injury and accelerant of graft rejection. Current interventions to mitigate IRI and promote tissue preservation are limited in their ability to provide cytoprotection, in part as a result of incomplete knowledge of the molecular mechanisms controlling IRI. Signal inhibitor regulatory protein alpha (SIRP-Α) is a cell surface receptor expressed on inflammatory cells with its dominant function believed to be suppression of macrophage phagocytosis. We now identify an unsuspected role for non-phagocytic SIRP-Α in promoting renal IRI. In hypoxic cells in vitro and following murine IRI, the secreted stress protein thrombospondin-1 (TSP1) binds to and directly activates non-phagocytic SIRP-Α and its cellular transducer SH2-domain-containing protein tyrosine pyrophosphatase 1 (SHP1), to stimulate NADPH oxidase (Nox) assembly and induce pathologic reactive oxygen species (ROS) production. IRI-mediated induction of TSP1-SIRP-Α signaling in vascular smooth muscle cells acutely limits, in a Nox-dependent ROS-mediated manner, vasodilation and tissue perfusion. In isolated renal tubular epithelial cells (rTEC), activation of non-phagocytic SIRP-Α via TSP1 promotes cell death via Nox-driven superoxide (O2−) production. Conversely, disrupting IRI-mediated TSP1-SIRP-Α signaling restores renal blood flow to pre-IRI levels, abrogates Nox-derived O2− production, prevents renal parenchymal cell death and abrogates pro-inflammatory cytokine production. These data, for the first time demonstrate a role for matrix cellular protein TSP1, via non-phagocytic SIRP-Α, as a proximate activator of Nox to increase pathologic ROS and promote IRI. They further suggest non-phagocytic SIRP-Α is a target to mitigate IRI-mediated organ transplant injury.
To cite this abstract in AMA style:Rogers N, Yao M, Csanyi G, Rodrigues A, Pagano P, Thomson A, Isenberg J. Matrix Cellular Activation of Non-Phagocytic SIRP-α Stimulates NADPH-Oxidase To Promote Cell Death, Limit Blood Flow and Promote Renal Ischemia Reperfusion Injury [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/matrix-cellular-activation-of-non-phagocytic-sirp-stimulates-nadph-oxidase-to-promote-cell-death-limit-blood-flow-and-promote-renal-ischemia-reperfusion-injury/. Accessed July 31, 2021.
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