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Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury

Zhao, Y;Xiong, Z;Lechner, EJ;Klenotic, PA;Hamburg, BJ;Hulver, M;Khare, A;Oriss, T;Mangalmurti, N;Chan, Y;Zhang, Y;Ross, MA;Stolz, DB;Rosengart, MR;Pilewski, J;Ray, P;Ray, A;Silverstein, RL;Lee, JS;

Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin (TSP)-1 (thbs1/), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to lipopolysaccharide-induced lung injury and show defective macrophage interleukin (IL)-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1/ mice from persistent neutrophilic lung inflammation and injury and thbs1/ alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co-culture with apoptotic neutrophils, thbs1/ macrophages show a selective defect in IL-10 production, whereas prostaglandin E2 and transforming growth factor beta 1 responses remain intact. Full macrophage IL-10 responses require the engagement of TSP-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages.