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.
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Kara L
KL
Conway
Gautam
G
Goel
Harry
H
Sokol
Monika
M
Manocha
Emiko
E
Mizoguchi
Cox
C
Terhorst
Atul K
AK
Bhan
Agnès
A
Gardet
Ramnik J
RJ
Xavier
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000502:physiology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012799:Sialyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology
D010750:Phosphoproteins; C085072:neutrophil cytosol factor 40K; D016264:Dextran Sulfate; D019255:NADPH Oxidases; D005647:Fucosyltransferases; D012799:Sialyltransferases