p40phox expression regulates neutrophil recruitment and function during the resolution phase of intestinal inflammation.
NADPH oxidase is a multisubunit complex that assembles during phagocytosis to generate reactive oxygen species. Several components of this complex have been implicated in chronic granulomatous disease and Crohn's disease, highlighting the importance of reactive oxygen species in regulating host immune response. In this study, we use genetically deficient mice to elucidate how p40(phox), one subunit of the NADPH oxidase complex, functions during intestinal inflammation. We show that p40(phox) deficiency enhances inflammation in both dextran sulfate sodium-induced and innate immune-mediated murine colitis models. This inflammation is characterized by severe colonic tissue injury, increased proinflammatory cytokines, and increased neutrophil recruitment. We demonstrate that neutrophils are essential during the recovery phase of intestinal inflammation and that p40(phox) expression is necessary for this restitution. Lastly, using an integrative bioinformatic approach, we show that p40(phox) deficiency leads to upregulation of chemokine receptor 1 and downregulation of enzymes involved in glycan modifications, including fucosyltransferases and sialyltransferases, during inflammation. We propose that p40(phox) deficiency enhances intestinal inflammation through the dysregulation of these two pathways in neutrophils.
|Year of Publication||
2012 Oct 01
|PubMed Central ID||
AI062773 / AI / NIAID NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States
RC1 DK086502 / DK / NIDDK NIH HHS / United States
R01 DK060049 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
DK060049 / DK / NIDDK NIH HHS / United States
R01 AI062773 / AI / NIAID NIH HHS / United States
R01 DK052510 / DK / NIDDK NIH HHS / United States
DK086502 / DK / NIDDK NIH HHS / United States
DK52510 / DK / NIDDK NIH HHS / United States