Work

CCL9/CCR1 chemokine signaling plays a protective role in limiting intestinal inflammation by maintaining an anti-inflammatory M2 macrophage pool in the intestinal lamina propria

Year: 2025

Type: article

Abstract: Inflammatory bowel diseases (IBD) are chronic disorders characterized by dysregulated immune responses and chemokines regulate immune cell trafficking in the intestinal mucosa. CCL9, a murine chemokine mediated by CCR1, is preferentially expressed in the intestinal tract, yet its role in intestinal inflammation remains unclear. We generated Ccl9 -/- and Ccr1 -/- mice using CRISPR/Cas9 and subjected them to dextran sulfate sodium (DSS)-induced colitis to investigate the role of CCL9/CCR1 axis. Both mutants developed more severe colitis than wild-type controls, with greater weight loss, colon shortening, histopathological damage, and enhanced pro-inflammatory cytokine production. In the steady state, most colonic macrophages were M2-like and expressed CCR1, but disruption of CCL9/CCR1 signaling reduced M2-like macrophages and expanded pro-inflammatory M1-like macrophages. In addition, loss of CCL9 or CCR1 induced compensatory upregulation of CCL2, CCL3 and CCL5, contributing to a pro-inflammatory environment. These findings identify CCL9 as an anti-inflammatory chemokine that sustains M2 macrophages, restrains excessive M1 expansion and limits intestinal inflammation. Targeting the CCL9/CCR1 axis may provide new therapeutic opportunities for IBD. • Pathological role of CCL9–CCR1 axis in colitis has not been clarified • We generated CRISPR/Cas9-mediated CCL9-KO and CCR1-KO mice on C57BL/6 background • Both mutant mice developed more severe DSS-induced colitis than WT controls • Loss of CCL9/CCR1 increased pro-inflammatory M1 and reduced anti-inflammatory M2 macrophages • CCL9–CCR1 axis acts as anti-inflammatory regulator of mucosal immune homeostasis

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.152763