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

Abstract

Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin-1 (thbs1−/−), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to LPS-induced lung injury and show defective macrophage 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 PGE2 and TGF-β1 responses remain intact. Full macrophage IL-10 responses require the engagement of thrombospondin-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.