title: NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis.
abstract: The leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generates reactive oxygen species essential in microbial killing and regulation of inflammation. Inactivating mutations in this enzyme lead to chronic granulomatous disease (CGD), associated with increased susceptibility to both pyogenic infections and to inflammatory disorders. The role of the NADPH oxidase in regulating inflammation driven by nonmicrobial stimuli is poorly understood. Here, we show that NADPH oxidase deficiency enhances the early local release of interleukin-1α (IL-1α) in response to damaged cells, promoting an excessive granulocyte colony-stimulating factor (G-CSF)-regulated neutrophilic response and prolonged inflammation. In peritoneal inflammation elicited by tissue injury, X-linked Cybb-null (X-CGD) mice exhibited increased release of IL-1α and IL-1 receptor -mediated G-CSF production. In turn, higher levels of systemic G-CSF increased peripheral neutrophilia, which amplified neutrophilic peritoneal inflammation in X-CGD mice. Dampening early neutrophil recruitment by neutralization of IL-1α, G-CSF, or neutrophil depletion itself promoted resolution of otherwise prolonged inflammation in X-CGD. IL-1β played little role. Thus, we identified an excessive IL-1α/G-CSF response as a major driver of enhanced sterile inflammation in CGD in the response to damaged cells. More broadly, these results provide new insights into the regulation of sterile inflammation, and identify the NADPH oxidase in regulating the amplitude of the early neutrophilic response.
authors.affiliation: Department of Pediatrics and.
authors.forename: Juhi
authors.initials: J
authors.lastname: Bagaitkar
authors.affiliation: Department of Pediatrics and.
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pech
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO; and.
authors.forename: Stoyan
authors.initials: S
authors.lastname: Ivanov
authors.affiliation: Department of Pediatrics and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Austin
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Melody Yue
authors.identifier: http://orcid.org/0000-0001-9044-6556
authors.initials: MY
authors.lastname: Zeng
authors.affiliation: Department of Pediatrics and.
authors.forename: Sabine
authors.identifier: http://orcid.org/0000-0002-6935-5649
authors.initials: S
authors.lastname: Pallat
authors.affiliation: Department of Pediatrics and.
authors.forename: Guangming
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO; and.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Department of Pediatrics and Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO; and.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology*; D006105:Granulomatous Disease, Chronic / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D053582:Interleukin-1alpha; D016179:Granulocyte Colony-Stimulating Factor; D019255:NADPH Oxidases