Efferocytosis induces macrophages to produce IL-4 and activate invariant NKT cells to suppress inflammation (117.17)

Abstract

Abstract Efferocytosis of apoptotic neutrophils by macrophages is fundamental to the resolution of inflammation. In this study we demonstrate using a mouse sterile peritonitis model, a circuit requiring the activation of NKT cells by efferocytosing macrophages to resolve inflammation. Following ingestion of apoptotic neutrophils, macrophages produced IL-4 and IL-13, which in an autocrine manner, resulted in cells with an M2 phenotype. Efferocytosing macrophages displayed increased cell surface expression of CD1d and activated invariant NKT (iNKT) cells that produced IL-4 during the later phase of inflammation. Peritoneal inflammation was exaggerated in mice lacking IL-4 or NKT cells, suggesting both are required to suppress inflammation. Furthermore, sterile peritoneal inflammation was also enhanced and prolonged in NADPH oxidase-deficient mice with X-linked chronic granulomatous disease (X-CGD). We found that X-CGD exudate macrophages expressed reduced surface CD1d and were impaired in activating iNKT cells, which contributed to the persistent inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation.