Pravastatin prevents colitis-associated carcinogenesis by reducing CX3CR1high M2-like fibrocyte counts in the inflamed colon

Colorectal cancer (CRC) resulting from chronic inflammation is a crucial issue in patients with inflammatory bowel disease (IBD). Although many reports established that intestinal resident CX3CR1^high macrophages play an essential role in suppressing intestinal inflammation, their function in colitis-related CRC remains unclear. In this study, we found that colonic CX3CR1^high macrophages, which were positive for MHC-II, F4/80 and CD319, promoted colitis-associated CRC. They highly expressed Col1a1, Tgfb, II10, and II4, and were considered to be fibrocytes with an immunosuppressive M2-like phenotype. CX3CR1 deficiency led to reductions in the absolute numbers of CX3CR1^high fibrocytes through increased apoptosis, thereby preventing the development of colitis-associated CRC. We next focused statins as drugs targeting CX3CR1^high fibrocytes. Statins have been actively discussed for patients with IBD and reported to suppress the CX3CL1/CX3CR1 axis. Statin treatment after azoxymethane/dextran sulfate sodium-induced inflammation reduced CX3CR1^high fibrocyte counts and suppressed colitis-associated CRC. Therefore, CX3CR1^high fibrocytes represent a potential target for carcinogenesis-preventing therapy, and statins could be safe therapeutic candidates for IBD.