title: Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.
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 (Ms) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse M populations from CGD (gp91(phox)(-/-)) and wild-type mice, as well as human Ms 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 M 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 Ms. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Ms restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.
authors.affiliation: National Jewish Health, Denver, CO 80206, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Fernandez-Boyanapalli
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: McPhillips
authors.forename: S Courtney
authors.initials: SC
authors.lastname: Frasch
authors.forename: William J
authors.initials: WJ
authors.lastname: Janssen
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: Aideen
authors.initials: A
authors.lastname: Byrne
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D004789:Enzyme Activation / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D009569:Nitric Oxide; D007371:Interferon-gamma
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