NOX1/NADPH oxidase in bone marrow-derived cells modulates intestinal barrier function

Area of Science:

• Biochemistry
• Immunology
• Gastroenterology

Background:

• Reactive oxygen species (ROS) are implicated in inflammatory bowel disease (IBD) pathogenesis.
• Intestinal barrier dysfunction is a hallmark of IBD.
• NOX1/NADPH oxidase is a significant ROS source in nonphagocytic cells.

Purpose of the Study:

• To investigate the role of NOX1 in intestinal barrier dysfunction.
• To elucidate the source of ROS contributing to IBD-related barrier defects.

Main Methods:

• In vivo and ex vivo imaging of ROS production in mice using L-012 probe.
• Assessment of intestinal hyperpermeability using fluorescein isothiocyanate-conjugated dextran (FD-4).
• Immunostaining for NOX1 and 3-nitrotyrosine.
• Bone marrow transplantation experiments.
• Analysis of matrix metalloproteinase-9 (MMP-9) activation and inducible nitric oxide synthase (iNOS) expression.

Main Results:

• LPS administration increased ROS in wild-type mice, significantly reduced in Nox1-deficient (Nox1-KO) and iNOS-deficient (iNOS-KO) mice.
• Increased ROS production and NOX1 expression were observed in the ileum.
• LPS-induced intestinal hyperpermeability was suppressed in Nox1-KO and iNOS-KO mice.
• NOX1 in bone marrow-derived cells, not epithelial cells, was responsible for perturbing intestinal barrier integrity.
• NOX1 deficiency alleviated LPS-induced MMP-9 activation and iNOS up-regulation.

Conclusions:

• NOX1 in bone marrow-derived cells is critical for intestinal barrier dysfunction during endotoxemia.
• NOX1 regulates iNOS expression, establishing a NOX1/iNOS signaling hierarchy.
• Targeting NOX1 may offer a therapeutic strategy for IBD.