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BLOOD ADVANCES
卷 7, 期 7, 页码 1225-1240出版社
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DOI: 10.1182/bloodadvances.2022007652
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The deficiency of NOX2 in neutrophils leads to excessive inflammation in chronic granulomatous disease (CGD), which is associated with recurrent infections and tissue damage. In this study, excessive production of LTB4 by NOX2-deficient neutrophils was found to drive elevated lung neutrophil infiltration. IL-1β and G-CSF were identified as critical signals that amplify and sustain neutrophil accumulation in CGD mice. Neutrophils were the primary source of IL-1β in the airways, and the increased number of neutrophils in CGD mice led to elevated local and plasma G-CSF. Elevated G-CSF promoted increased granulopoiesis and mobilized the release of an immature neutrophil subset from the marrow, which exhibited a more proinflammatory transcriptome. These findings highlight NOX2 as a key regulator of neutrophil number, subsets, and function in inflammation.
The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its antimicrobial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 (LTB4) production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the model fungal particle zymosan. We now identify interleukin-1(3 (IL-1(3) and downstream granulocyte colony-stimulating factor (G-CSF) as critical amplifying signals that augment and sustain neutrophil accrual in CGD mice. Neutrophils, delivered into the lung via LTB4, were the primary source of IL-1(3 within the airways, and their increased numbers in CGD lungs led to significantly elevated local and plasma G-CSF. Elevated G-CSF simultaneously promoted increased granulopoiesis and mobilized the release of higher numbers of an immature CD101- neutrophil subset from the marrow, which trafficked to the lung and acquired a significantly more proinflammatory transcriptome in CGD mice compared with wild-type mice. Thus, neutrophil-produced IL-1(3 and downstream G-CSF act sequentially but nonredundantly with LTB4 to deploy neutrophils and amplify inflammation in CGD mice after inhalation of zymosan. NOX2 plays a critical role in dampening multiple components of a feed-forward pipeline for neutrophil recruitment, and these findings highlight NOX2 as a key regulator of neutrophil number, subsets, and function at inflamed sites.
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