Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner

R Fernandez-Boyanapalli, KA McPhillips… - The Journal of …, 2010 - journals.aai.org
R Fernandez-Boyanapalli, KA McPhillips, SC Frasch, WJ Janssen, MC Dinauer…
The Journal of Immunology, 2010journals.aai.org
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 (Mϕs) with
IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse Mϕ
populations from CGD (gp91 phox−/−) and wild-type mice, as well as human Mϕs …
Abstract
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 (Mϕs) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse Mϕ populations from CGD (gp91 phox−/−) and wild-type mice, as well as human Mϕs 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-γ priming. Priming with IFN-γ 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-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by Mϕ in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Mϕs. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Mϕs restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.
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