Mairin polarizes Macrophages into M2-phenotype and alleviates Ulcerative colitis through activating IRF4-CD5L pathway

Ulcerative colitis (UC) is a recurrent inflammatory bowel disease characterized by mucosal inflammation. Recently, the incidence rate of UC increases year by year, and patients diagnosed with UC usually have the poor quality of life. The search for effective treatments of UC remains a crucial research priority. Since traditional Chinese medicine (TCM) is an important treatment for UC, the components of these TCMs were analyzed. Our data indicated that Mairin was the common core component of TCMs with UC therapeutic effects, including Licorice, Paeoniae Radix Alba and Aucklandiae Radix. Recently, only one study reported that the hydroxamate of Mairin prevented colonic inflammation and fibrosis, and the function and mechanism of Mairin on UC were still obscure. Dextran sulfate sodium (DSS)-induced UC mice were alleviated after Mairin treatment. Mechanistically, RNA sequencing data indicated that Mairin treatment increased the levels of Irf4 and Cd5l. Molecular docking, drug affinity responsive target stability (DARTS) and immunofluorescence experiments were used to verify that Mairin interacted with EGFR and SRC, promoted IRF4 nuclear import in macrophages. ChIP analysis was verified that IRF4, as a transcription factor, interacted with Cd5l promoter, and Mairin treatment increased the mRNA and protein levels of CD5L. CD5L⁺ macrophages exhibited the high level of M2 phenotype markers, and M2-phenotype macrophages alleviated UC. That was to say, Mairin activated IRF4-CD5L pathway, polarized macrophages into M2-phenotype, and alleviated UC. Our study contributes to the exploration the therapeutic mechanism of Mairin and it also may provide insights for new therapeutic medicine of UC.