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The underlying mechanisms of intestinal fibrosis remain largely elusive. Reanalysis of the single\u2010cell RNA\u2010seq data from full\u2010thickness CD tissue identifies a distinct profibrotic macrophage subset characterized by high\n                    <jats:italic>S100A8<\/jats:italic>\n                    and\n                    <jats:italic>S100A9<\/jats:italic>\n                    expression. CellChat analysis indicates strong communication between this S100A8\/A9\u2010high (S100A8\/A9\n                    <jats:sup>hi<\/jats:sup>\n                    ) macrophage subset and fibroblasts. Adoptive transfer of S100A8\/A9\n                    <jats:sup>hi<\/jats:sup>\n                    macrophages exacerbate intestinal fibrosis in mice with chronic dextran sulfate sodium (DSS)\u2010induced colitis. Consequently, pharmacological inhibition of S100A8\/A9 significantly ameliorates intestinal fibrosis in murine chronic colitis. Proteomic analysis further identifies murine CCL6 (mCCL6) as the key pro\u2010fibrotic mediator secreted by S100A8\/A9\n                    <jats:sup>hi<\/jats:sup>\n                    macrophages, which acts via CC chemokine receptor 1 (CCR1) to regulate fibroblasts. Antibody blockade of mCCL6 alleviates established intestinal fibrosis in a DSS\u2010induced colitis model. Mechanistically, S100A8\/A9\n                    <jats:sup>hi<\/jats:sup>\n                    macrophages drive mCCL6 production via STAT3 activation. Similarly, the human ortholog of CCL6, CCL15 (hCCL15), exerts pro\u2010fibrotic effects on fibroblasts via the CCR1 receptor. Our findings reveal that targeting S100A8\/A9\n                    <jats:sup>hi<\/jats:sup>\n                    macrophage may be a therapeutic strategy against intestinal fibrosis in CD.\n                  <\/jats:p>","DOI":"10.1002\/advs.76353","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:47:08Z","timestamp":1782751628000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["S100A8\/A9\u2010High Macrophages Activate Intestinal Fibroblasts via mCCL6\/hCCL15\u2010CCR1 Axis to Drive Intestinal Fibrosis in Crohn's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Shu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital with Nanjing Medical University  Nanjing Jiangsu 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