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NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures
Nai-Yun Hsu1, Shikha Nayar2, Kyle Gettler1
1Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Gut
|October 3, 2022
Summary
Loss of NOX1 function and reactive oxygen species (ROS) dysregulate the stem cell niche, contributing to colitis. Restoring ROS may offer new therapeutic strategies for inflammatory bowel disease (IBD).
Area of Science:
- Gastroenterology and Immunology
- Cell Biology and Molecular Mechanisms
- Inflammatory Bowel Disease (IBD) Pathogenesis
Background:
- Loss-of-function mutations in genes producing reactive oxygen species (ROS), such as NOX1, are linked to inflammatory bowel disease (IBD).
- The precise mechanisms by which reduced ROS contribute to IBD development remain unclear.
Purpose of the Study:
- To investigate the role of NOX1 and ROS in the pathogenesis of IBD.
- To elucidate how NOX1 deficiency impacts colonoid function and cell differentiation.
- To identify potential therapeutic targets for IBD based on ROS modulation.
Main Methods:
- Comparative analysis of ROS production in NOX1-wild-type versus NOX1-deficient murine colonoids under TNFα stimulation.
- Single-cell RNA sequencing (scRNASeq) of human ulcerative colitis (UC) epithelial cells and in vitro colonoids.
- Immunohistochemistry (UEA1 staining) and in vivo dextran sodium sulfate (DSS) injury models to validate M cell induction and stem cell niche alterations.
Main Results:
- NOX1-deficient colonoids exhibited significantly lower baseline expression of key transcription factors (STAT3, CEBPD, DNMT1, HIF1A) and reduced ROS production.
- Unexpectedly, NOX1-deficient colonoids showed marked TNFα-mediated induction of M cells, which was rescued by exogenous ROS (H₂O₂ and paraquat).
- DSS-induced colitis in NOX1-deficient models showed increased glycoprotein-2 (GP2), basal lymphoplasmacytosis, and M cell markers, correlating with UC inflammation.
Conclusions:
- NOX1 deficiency, coupled with TNFα stimulation, promotes colitis by disrupting the stem cell niche and altering epithelial cell differentiation, leading to increased lymphoplasmacytosis.
- The findings highlight the critical role of ROS in maintaining stem cell function and regulating immune responses in the gut.
- Modulation of ROS presents a promising therapeutic avenue for treating IBD.
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