(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway

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Compound edaravone injection (C.EDA), a compound preparation composed of edaravone (EDA) and (+)-Borneol with the mass ratio of 4: 1, displays a better anti-inflammatory activity than EDA. However, its precise mechanism remains to be further studied. In this work, we investigated whether (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis. We found that C.EDA at 7.5 and 15 mg/kg could significantly relieve the disease activity index (DAI) and reduce the loss of body weight and colon length in a dose-dependent manner, while EDA or (+)-Borneol alone only had moderate effects even at the highest dose. Additionally, ELISA revealed that C.EDA could more dramatically decrease the protein levels of inflammatory cytokines and increase the levels of anti-inflammatory cytokine than EDA or (+)-Borneol alone both in colon tissues and serum. H&E staining and IHC assay also indicated that C.EDA exhibited more prominent effects on increasing the population of M2 macrophages, decreasing M1 macrophages infiltration and protecting intestinal barrier integrity. Furthermore, in vitro studied demonstrated that C.EDA, EDA or (+)-Borneol failed in inhibiting M1 macrophages activation but could specifically induce the activation of M2 macrophages in a STAT3-dependent manner. Knockdown the expression of STAT3 successfully abolished the effect of C.EDA and EDA on promoting M2 macrophages activation. Consistent with in vivo study, C.EDA exhibited a more efficient ability of inducing M2 macrophages polarization and STAT3 activation than EDA or (+)-Borneol alone in vitro. In conclusion, we confirmed that (+)-Borneol improved the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.Graphical abstractHighlights(+)-Borneol improved the efficacy of EDA against DSS-induced colitis.C.EDA inhibited the infiltration of M1 macrophages, promoted the polarization of M2 macrophages and protected the integrity of colon tissue.C.EDA greatly promoted M2 macrophages polarization in Raw264.7 cellsC.EDA strengthened the activation of JAK2-STAT3 signaling pathway and promoted STAT3 nuclear translocationSTAT3-specific RNA interference successfully abolished the effects of C.EDA on inducing M2 macrophages polarization

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