Impaired Phagocytosis of Apoptotic Cells by Macrophages in Chronic Granulomatous Disease Is Reversed by IFN-γ in a Nitric Oxide-Dependent Manner

Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (M phi s) with IFN-gamma would enhance impaired engulfment of apoptotic cells in CGD. Diverse M phi populations from CGD (gp91(phox-/-)) and wild-type mice, as well as human M phi s differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91(phox)), demonstrated enhanced engulfment of apoptotic cells in response to IFN-gamma priming. Priming with IFN-gamma was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-gamma priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-alpha in response to IFN-gamma priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-gamma also enhanced uptake of apoptotic cells by Mf in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-gamma treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Mfs. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-gamma priming of Mfs restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation. The Journal of Immunology, 2010, 185: 4030-4041.