Matrix Cellular Activation of Non-Phagocytic SIRP-α Stimulates NADPH-Oxidase To Promote Cell Death, Limit Blood Flow and Promote Renal Ischemia Reperfusion Injury
Department of Medicine, University of Pittsburgh, Pittsburgh, PA
Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
Meeting: 2013 American Transplant Congress
Abstract number: 116
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 October 9, 2024.« Back to 2013 American Transplant Congress