Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis
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 epithelia...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI163591 |
| _version_ | 1827768112948183040 |
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| author | Efren A. Reyes David Castillo-Azofeifa Jérémie Rispal Tomas Wald Rachel K. Zwick Brisa Palikuqi Angela Mujukian Shervin Rabizadeh Alexander R. Gupta James M. Gardner Dario Boffelli Zev J. Gartner Ophir D. Klein |
| author_facet | Efren A. Reyes David Castillo-Azofeifa Jérémie Rispal Tomas Wald Rachel K. Zwick Brisa Palikuqi Angela Mujukian Shervin Rabizadeh Alexander R. Gupta James M. Gardner Dario Boffelli Zev J. Gartner Ophir D. Klein |
| author_sort | Efren A. Reyes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:43Z |
| format | Article |
| id | doaj.art-6e8bbf33ec144be58c7912b2853fe1d7 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:43Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-6e8bbf33ec144be58c7912b2853fe1d72023-11-07T16:20:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113320Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasisEfren A. ReyesDavid Castillo-AzofeifaJérémie RispalTomas WaldRachel K. ZwickBrisa PalikuqiAngela MujukianShervin RabizadehAlexander R. GuptaJames M. GardnerDario BoffelliZev J. GartnerOphir D. KleinThe 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.https://doi.org/10.1172/JCI163591Gastroenterology |
| spellingShingle | Efren A. Reyes David Castillo-Azofeifa Jérémie Rispal Tomas Wald Rachel K. Zwick Brisa Palikuqi Angela Mujukian Shervin Rabizadeh Alexander R. Gupta James M. Gardner Dario Boffelli Zev J. Gartner Ophir D. Klein Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis The Journal of Clinical Investigation Gastroenterology |
| title | Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis |
| title_full | Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis |
| title_fullStr | Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis |
| title_full_unstemmed | Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis |
| title_short | Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis |
| title_sort | epithelial tnf controls cell differentiation and cftr activity to maintain intestinal mucin homeostasis |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/JCI163591 |
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