S100A8/A9‐High Macrophages Activate Intestinal Fibroblasts via mCCL6/hCCL15‐CCR1 Axis to Drive Intestinal Fibrosis in Crohn's Disease

ABSTRACT Intestinal fibrosis presents a major clinical challenge in Crohn's disease (CD) due to the lack of effective pharmacological interventions. The underlying mechanisms of intestinal fibrosis remain largely elusive. Reanalysis of the single‐cell RNA‐seq data from full‐thickness CD tissue identifies a distinct profibrotic macrophage subset characterized by high S100A8 and S100A9 expression. CellChat analysis indicates strong communication between this S100A8/A9‐high (S100A8/A9 hi ) macrophage subset and fibroblasts. Adoptive transfer of S100A8/A9 hi macrophages exacerbate intestinal fibrosis in mice with chronic dextran sulfate sodium (DSS)‐induced 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‐fibrotic mediator secreted by S100A8/A9 hi macrophages, which acts via CC chemokine receptor 1 (CCR1) to regulate fibroblasts. Antibody blockade of mCCL6 alleviates established intestinal fibrosis in a DSS‐induced colitis model. Mechanistically, S100A8/A9 hi macrophages drive mCCL6 production via STAT3 activation. Similarly, the human ortholog of CCL6, CCL15 (hCCL15), exerts pro‐fibrotic effects on fibroblasts via the CCR1 receptor. Our findings reveal that targeting S100A8/A9 hi macrophage may be a therapeutic strategy against intestinal fibrosis in CD.