Emergence of NOX1/DUOX NADPH oxidases is a key feature of functional neutrophil reprogramming at the gut and lung barrier

Functional neutrophil diversity is recognized as a driver of development, progression and resolution of disease. Recruited neutrophils are imprinted by biochemical, biophysical and mechanical stimuli of the encountered microenvironment, altering their genetic and phenotypic program. The functional implications of this reprogramming are of critical importance for devising strategies to modify neutrophil behavior. Oxidant production affects neutrophil responses, shapes the microenvironment and often determines disease outcome in inflammation, infection and cancer. Here we report neutrophil diversification at mucosal barriers in inflammatory and infectious disease, culminating in tissue and stimulus-dependent de novo expression of the NADPH oxidases NOX1, DUOX2, and DUOX1 in recruited neutrophils. In contrast to proinflammatory DUOX2, myeloid NOX1 ameliorated colonic inflammation, yet epithelial NOX1 increased neutrophil recruitment from the onset, with a similar response observed in pulmonary S. aureus infection. In contrast, neutrophil DUOX expression did not alter S. aureus disease progression but extended host survival in influenza A virus infection. Thus, at gut and lung barriers an expansion of neutrophil oxidases occurs that highlights proinflammatory and antimicrobial DUOX2 activity, while NOX1 function seems intricate with multiple inputs. Evaluation of these de novo expressed oxidases in other neutrophil-driven diseases will further uncover their contribution to host protection and pathogenesis.