1. Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis
- Author
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Reyes, Efren A, Castillo-Azofeifa, David, Rispal, Jérémie, Wald, Tomas, Zwick, Rachel K, Palikuqi, Brisa, Mujukian, Angela, Rabizadeh, Shervin, Gupta, Alexander R, Gardner, James M, Boffelli, Dario, Gartner, Zev J, and Klein, Ophir D
- Subjects
Biological Sciences ,Medical Physiology ,Biomedical and Clinical Sciences ,Stem Cell Research ,Cystic Fibrosis ,Digestive Diseases ,Autoimmune Disease ,Lung ,Crohn's Disease ,Rare Diseases ,Inflammatory Bowel Disease ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Humans ,Animals ,Mice ,Mucins ,Cystic Fibrosis Transmembrane Conductance Regulator ,Tumor Necrosis Factor Inhibitors ,Epithelial Cells ,Cell Differentiation ,Tumor Necrosis Factors ,Homeostasis ,Cytokines ,Epithelial transport of ions and water ,Gastroenterology ,Molecular genetics ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.
- Published
- 2023