{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:53:07Z","timestamp":1781844787051,"version":"3.54.5"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Macrophages play a central role in regulating intestinal inflammation, resolution, and tissue repair. However, the upstream regulators that govern their polarization during colitis remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we used a dextran sulfate sodium (DSS)-induced colitis model to investigate the role of the scaffold protein AF6 in colitis pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identify AF6 as a key regulator that promotes pro-inflammatory macrophage polarization and exacerbates colitis. Mechanistically, AF6 expression promoted JAK-STAT3 complex formation. In turn, its deletion in macrophages resulted in impaired JAK-STAT3 signaling pathway and a shift away from pro-inflammatory M1 polarization. Furthermore, the AF6-deficient macrophages were determined to also promote epithelial regeneration through enhanced IL-10 production and downstream activation of Wnt\/\u03b2-catenin signaling in intestinal organoids culture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Thus, our study defines a therapeutically amenable AF6-JAK2-STAT3 axis that controls macrophage-driven pathogenesis in colitis, revealing a novel strategy to break the cycle of inflammation and impaired repair.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1798313","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:29:13Z","timestamp":1781843353000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["AF6 orchestrates macrophage polarization via JAK2-STAT3 signaling and supports intestinal regeneration by stimulating stem cell proliferation"],"prefix":"10.3389","volume":"17","author":[{"given":"Tao","family":"Jian","sequence":"first","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Dong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Kong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyan","family":"Qi","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Zhan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences","place":["Shanghai, China"]},{"name":"Yiwu Central Hospital, the Affiliated Yiwu Hospital of Wenzhou Medical University","place":["Yiwu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilei","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Yiwu Central Hospital, the Affiliated Yiwu Hospital of Wenzhou Medical University","place":["Yiwu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrgastro.2016.169","article-title":"The intestinal epithelial barrier: a therapeutic target","volume":"14","author":"Odenwald","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.010908.163145","article-title":"Stem cells, self-renewal, and differentiation in the intestinal epithelium","volume":"71","author":"van der Flier","year":"2009","journal-title":"Annu Rev Physiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.583919","article-title":"Regenerative intestinal stem cells induced by acute and chronic injury: the saving grace of the epithelium","volume":"8","author":"Rees","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.09.010","article-title":"Metabolic support by macrophages sustains colonic epithelial homeostasis","volume":"35","author":"Fritsch","year":"2023","journal-title":"Cell Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13771","article-title":"Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease","volume":"283","author":"Blander","year":"2016","journal-title":"FEBS J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pop.2023.03.009","article-title":"Inflammatory bowel disease","volume":"50","author":"Bruner","year":"2023","journal-title":"Prim Care"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0415-0","article-title":"Targeting immune cell circuits and trafficking in inflammatory bowel disease","volume":"20","author":"Neurath","year":"2019","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.08.021","article-title":"The role of intestinal macrophages in gastrointestinal homeostasis: heterogeneity and implications in disease","volume":"12","author":"Yip","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.123","article-title":"The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD","volume":"9","author":"Cos\u00edn-Roger","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00848-y","article-title":"Tissue-specific macrophages: how they develop and choreograph tissue biology","volume":"23","author":"Mass","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nri3088","article-title":"Transcriptional regulation of macrophage polarization: enabling diversity with identity","volume":"11","author":"Lawrence","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41392-023-01452-1","article-title":"Macrophages in immunoregulation and therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1186\/s12964-023-01386-9","article-title":"Macrophage polarization in inflammatory bowel disease","volume":"21","author":"Zhang","year":"2023","journal-title":"Cell Commun Signal"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070075","article-title":"Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis","volume":"204","author":"Arnold","year":"2007","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2020.1779318","article-title":"Baicalin regulates macrophages polarization and alleviates myocardial ischaemia\/reperfusion injury via inhibiting JAK\/STAT pathway","volume":"58","author":"Xu","year":"2020","journal-title":"Pharm Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"154228","DOI":"10.1016\/j.phymed.2022.154228","article-title":"Viola yedoensis Makino formula alleviates DNCB-induced atopic dermatitis by activating JAK2\/STAT3 signaling pathway and promoting M2 macrophages polarization","volume":"103","author":"Zeng","year":"2022","journal-title":"Phytomedicine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"8184","DOI":"10.1038\/ncomms8184","article-title":"Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression","volume":"6","author":"Xu","year":"2015","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0695","article-title":"Polarity protein AF6 controls hepatic glucose homeostasis and insulin sensitivity by modulating IRS1\/AKT insulin pathway in an SHP2-dependent manner","volume":"68","author":"Dai","year":"2019","journal-title":"Diabetes"},{"key":"B19","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41419-023-06170-8","article-title":"Polarity protein AF6 functions as a modulator of necroptosis by regulating ubiquitination of RIPK1 in liver diseases","volume":"14","author":"Xinyu","year":"2023","journal-title":"Cell Death Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/s0960-9822(99)80392-3","article-title":"Absence of the tight junctional protein AF-6 disrupts epithelial cell-cell junctions and cell polarity during mouse development","volume":"9","author":"Zhadanov","year":"1999","journal-title":"Curr Biol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s42003-021-01730-0","article-title":"Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494\/EDA2R\/\u03b2-catenin signaling in mice","volume":"4","author":"Song","year":"2021","journal-title":"Commun Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-52057-0_5","article-title":"JAK\u2013STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects","volume":"77","author":"Banerjee","year":"2017","journal-title":"Drugs"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1791","article-title":"Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis","volume":"10","author":"Murai","year":"2009","journal-title":"Nat Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/mpg.0000000000002937","article-title":"Predictive prenatal diagnosis for infantile-onset inflammatory bowel disease because of interleukin-10 signalling defects","volume":"72","author":"Ye","year":"2021","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1038\/s41598-018-38125-x","article-title":"IL-10 produced by macrophages regulates epithelial integrity in the small intestine","volume":"9","author":"Morhardt","year":"2019","journal-title":"Sci Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1172\/jci90229","article-title":"Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling","volume":"127","author":"Quiros","year":"2017","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1798313\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:29:14Z","timestamp":1781843354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1798313\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":26,"alternative-id":["10.3389\/fimmu.2026.1798313"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1798313","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"article-number":"1798313"}}