MKP‐1 promotes anti‐inflammatory M(IL‐4/IL‐13) macrophage phenotype and mediates the anti‐inflammatory effects of glucocorticoids

Abstract Macrophage polarization refers to the ability of these cells to adopt different functional phenotypes according to their environment. Mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) is known to regulate the classical lipopolysaccharide (LPS)‐induced pro‐inflammatory macrophage activation and the inflammatory response. Here, we investigated the effects of MKP‐1 on the anti‐inflammatory and healing‐promoting macrophage phenotype induced by cytokines IL‐4 and IL‐13 and examined the potential mediator role of MKP‐1 in glucocorticoid effects on the two macrophage phenotypes. In MKP‐1‐deficient macrophages treated with IL‐4 and IL‐13 to induce the anti‐inflammatory phenotype, the expression of phenotypic markers arginase 1, Ym‐1 and FGF2 was reduced as compared to wild‐type cells. In contrast, LPS‐induced expression of the pro‐inflammatory factors IL‐6 and iNOS was significantly higher in MKP‐1‐deficient macrophages. Dexamethasone suppressed the pro‐inflammatory phenotype and enhanced the anti‐inflammatory phenotype. Interestingly, both of these glucocorticoid effects were attenuated in macrophages from MKP‐1‐deficient mice. Accordingly, dexamethasone increased MKP‐1 expression in both LPS‐ and IL4+13‐treated wild‐type cells. In conclusion, the findings support MKP‐1 as an endogenous mechanism able to shift macrophage activation from the classical pro‐inflammatory state towards the anti‐inflammatory and healing‐promoting phenotype. In addition, MKP‐1 was found to mediate the anti‐inflammatory effects of dexamethasone in a dualistic manner: by suppressing the pro‐inflammatory macrophage activation and by enhancing the healing‐promoting macrophage phenotype.