{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:01:26Z","timestamp":1785416486106,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["#22\/262"],"award-info":[{"award-number":["#22\/262"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["24\/659\/A"],"award-info":[{"award-number":["24\/659\/A"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"award":["#22\/262"],"award-info":[{"award-number":["#22\/262"]}],"id":[{"id":"https:\/\/ror.org\/00zbf3d93","id-type":"ROR","asserted-by":"publisher"}]},{"award":["24\/659\/A"],"award-info":[{"award-number":["24\/659\/A"]}],"id":[{"id":"https:\/\/ror.org\/00zbf3d93","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed \u201cregenerative inflammation,\u201d in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF\u2013IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions.<\/jats:p>","DOI":"10.3390\/cells15131144","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:57:24Z","timestamp":1782287844000},"page":"1144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regenerative Inflammation in IBD: How Type I Interferons and TNF Cross-Talk Converts Epithelial Repair into Therapeutic Response"],"prefix":"10.3390","volume":"15","author":[{"given":"Emelia A. M.","family":"Hinton","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Division of Health Sciences, University of Otago, Dunedin P.O. Box 56, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roslyn A.","family":"Kemp","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Division of Health Sciences, University of Otago, Dunedin P.O. Box 56, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3116-0747","authenticated-orcid":false,"given":"Michael","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Health New Zealand Southern, Dunedin 9054, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8424-8355","authenticated-orcid":false,"given":"Safina","family":"Gadeock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Division of Health Sciences, University of Otago, Dunedin P.O. Box 56, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3748\/wjg.v29.i7.1157","article-title":"Mucosal healing and inflammatory bowel disease: Therapeutic implications and new targets","volume":"21","author":"Otte","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Marsal, J., Barreiro-de Acosta, M., Blumenstein, I., Cappello, M., Bazin, T., and Sebastian, S. (2022). Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front. 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