Neutrophils: Another Case of Wrongful Conviction?

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Science Translational Medicine  12 Feb 2014:
Vol. 6, Issue 223, pp. 223ec28
DOI: 10.1126/scitranslmed.3008643

People aren’t the only ones who get wrongfully convicted. Neutrophils are often blamed for tissue injury via the reactive oxygen intermediates they produce as part of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase respiratory burst during acute inflammation. Campbell and colleagues reopened the case against neutrophils as a contributor to mucosal injury during colitis in light of new evidence: Inflammatory lesions are hypoxic, and epithelial cells respond to hypoxia with a protective stress response mediated by the hypoxia-inducible factor (HIF) transcriptional regulator.

In a series of in vitro experiments, the authors showed that activated neutrophils deplete oxygen locally as part of the NADPH oxidase respiratory burst, and intestinal epithelial cells respond with increased HIF activity and expression of hypoxia responsive genes. Neutrophils with inhibited or defective NADPH oxidase systems did not deplete oxygen and failed to induce an epithelial HIF response. The authors confirmed their findings in vivo in the trinitrobenzenesulfonic acid (TNBS) mouse colitis model of acute colonic inflammation; in a subset of the mice, they depleted the neutrophils before TNBS exposure. Remarkably, the neutrophil-depleted mice had worse clinical disease and colonic mucosal injury after TNBS exposure than did mice with an intact neutrophil response and lacked the usual epithelial HIF response in the mucosa of mice. To verify that the beneficial effect of neutrophils was mediated by the respiratory burst, the authors repeated the same experiments with NADPH oxidase-deficient mice. In these mice, the connection between neutrophils and a HIF response was removed because of the lack of respiratory burst capability in neutrophils, and NADPH-deficient mice had a more severe colitis phenotype, similar to neutrophil-depleted mice after TNBS exposure. Last, the authors showed the relevance of their work to human disease by verifying representative findings in tissue biopsies from patients with ulcerative colitis and demonstrated the therapeutic potential of boosting HIF activity as a way to attenuate colitis in the TNBS mouse colitis model.

This study provides compelling evidence that neutrophils and the NADPH oxidase respiratory burst confer a net benefit on host epithelial cells in the setting of acute mucosal inflammation by depleting oxygen locally and triggering a protective hypoxic stress response. This conclusion is contrary to historic beliefs that reactive intermediates produced by the neutrophil respiratory burst were detrimental to host cells in some settings and has important implications for the treatment of human inflammatory diseases. Additional studies are needed to test the relationship between neutrophils and the epithelial HIF response in chronic inflammatory conditions and to evaluate the safety and effectiveness of HIF modulation in human inflammatory diseases.

E. L. Campbell et al., Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014). [Abstract]

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