GM-CSF-producing CCR2+ CCR6+ Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice

Genes Cells. 2023 Apr;28(4):267-276. doi: 10.1111/gtc.13008. Epub 2023 Jan 24.


Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C-C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2+ CCR6+ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2+ CCR6+ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.

Keywords: CCR2; CCR6; GM-CSF; colitis; inflammatory bowel disease; pathogenic Th17 cell.

MeSH terms

  • Animals
  • Chemokines / adverse effects
  • Colitis* / chemically induced
  • Colitis* / genetics
  • Dextrans / adverse effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / adverse effects
  • Inflammatory Bowel Diseases*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR2 / genetics
  • Receptors, CCR6 / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Th17 Cells / metabolism
  • Th17 Cells / pathology


  • Dextrans
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • sodium sulfate
  • Chemokines
  • CCR6 protein, mouse
  • Receptors, CCR6
  • Ccr2 protein, mouse
  • Receptors, CCR2