NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

Juhi Bagaitkar, Nancy K. Pech, Stoyan Ivanov, Anthony Austin, Melody Yue Zeng, Sabine Pallat, Guangming Huang, Gwendalyn J. Randolph, Mary C. Dinauer

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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-CSFincreased 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 inX-CGD. IL-1β played little role. Thus,we identified anexcessive IL-1α/G-CSF response as amajor driver of enhanced sterile inflammation in CGD in the response to damaged cells.More broadly, these results provide newinsights into the regulation of sterile inflammation, and identify the NADPH oxidase in regulating the amplitude of the early neutrophilic response.

Original languageEnglish
Pages (from-to)2724-2733
Number of pages10
JournalBlood
Volume126
Issue number25
DOIs
StatePublished - Dec 17 2015

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