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

Y. Zhao, Z. Xiong, E. J. Lechner, P. A. Klenotic, B. J. Hamburg, M. Hulver, A. Khare, T. Oriss, N. Mangalmurti, Y. Chan, Y. Zhang, M. A. Ross, D. B. Stolz, M. R. Rosengart, J. Pilewski, P. Ray, A. Ray, R. L. Silverstein, J. S. Lee

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish
Pages (from-to)440-448
Number of pages9
JournalMucosal Immunology
Issue number2
StatePublished - Mar 2014


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