Role of p40phox in host defense against Citrobacter rodentium infection

FEBS Open Bio. 2021 May;11(5):1476-1486. doi: 10.1002/2211-5463.13155. Epub 2021 Apr 9.

Abstract

NADPH oxidase (NOX) is a membrane-bound enzyme complex that generates reactive oxygen species (ROS). Mutations in NOX subunit genes have been implicated in the pathogenesis of inflammatory bowel disease (IBD), indicating a crucial role for ROS in regulating host immune responses. In this study, we utilize genetically deficient mice to investigate whether defects in p40phox , one subunit of NOX, impair host immune response in the intestine and aggravate disease in an infection-based (Citrobacter rodentium) model of colitis. We show that p40phox deficiency does not increase susceptibility of mice to C. rodentium infection, as no differences in body weight loss, bacterial clearance, colonic pathology, cytokine production, or immune cell recruitment were observed between p40phox-/- and wild-type mice. Interestingly, higher IL-10 levels were observed in the supernatants of MLN cells and splenocytes isolated from infected p40phox -deficient mice. Further, a higher expression level of inducible nitric oxide synthase (iNOS) was also noted in mice lacking p40phox . In contrast to wild-type mice, p40phox-/- mice exhibited greater NO production after LPS or bacterial antigen re-stimulation. These results suggest that p40phox-/- mice do not develop worsened colitis. While the precise mechanisms are unclear, it may involve the observed alteration in cytokine responses and enhancement in levels of iNOS and NO.

Keywords: C. rodentium; IBD; colonic inflammation; p40phox.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • China
  • Citrobacter rodentium / pathogenicity
  • Colitis / physiopathology
  • Colon / immunology
  • Colon / microbiology
  • Disease Models, Animal
  • Enterobacteriaceae Infections / metabolism*
  • Female
  • Immunity / genetics
  • Immunity / immunology
  • Inflammatory Bowel Diseases
  • Intestinal Mucosa / immunology
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphoproteins
  • Reactive Oxygen Species / metabolism
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism*

Substances

  • Lancl1 protein, mouse
  • Phosphoproteins
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • neutrophil cytosol factor 40K
  • Nitric Oxide Synthase Type II
  • NADPH Oxidases