Mdivi-1 Modulates Macrophage/Microglial Polarization in Mice with EAE via the Inhibition of the TLR2/4-GSK3ß-NF-κB Inflammatory Signaling Axis.

Macrophage/microglial modulation plays a critical role in the pathogenesis of multiple sclerosis (MS), which is an inflammatory disorder of the central nervous system. Dynamin-related protein 1 is a cytoplasmic molecule that regulates mitochondrial fission. It has been proven that mitochondrial fission inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, can relieve experimental autoimmune encephalomyelitis (EAE), a preclinical animal model of MS. Whether macrophages/microglia are involved in the pathological process of Mdivi-1-treated EAE remains to be determined. Here, we studied the anti-inflammatory effect of Mdivi-1 on mice with oligodendrocyte glycoprotein peptide35-55 (MOG35-55)-induced EAE. We found that Drp1 phosphorylation at serine 616 in macrophages/microglia was decreased with Mdivi-1 treatment, which was accompanied by decreased antigen presentation capacity of the macrophages/microglia in the EAE mouse spinal cord. The Mdivi-1 treatment caused macrophage/microglia to produce low levels of proinflammatory molecules, such as CD16/32, iNOS, and TNF-α, and high levels of anti-inflammatory molecules, such as CD206, IL-10, and Arginase-1, suggesting that Mdivi-1 promoted the macrophage/microglia shift from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Moreover, Mdivi-1 was able to downregulate the expression of TRL2, TRL4, GSK-3ß, and phosphorylated NF-κB-p65 and prevent NF-κB-mediated IL-1ß and IL-6 production. In conclusion, these results indicate that Mdivi-1 significantly alleviates inflammation in mice with EAE by promoting M2 polarization by inhibiting TLR2/4- and GSK3ß-mediated NF-κB activation.

[Dihydrotanshinone I (DHTS1) attenuates cuprizone-induced demyelination via regulating microglia polarization].

Objective To evaluate whether dihydrotanshinone I (DHTS1) attenuates cuprizone-induced demyelination. Methods DHTS1 was dissolved in 5 g/L sodium carboxymethyl cellulose (CMC-Na). The cuprizone model was induced via feeding with the diet containing 2 g/L cuprizone. We administrated DHTS1 to the cuprizone-exposed mice. The mice were randomly divided into CMC-Na normal group, CMC-Na combined with cuprizone group and DHTS1 combined with cuprizone group. Myelin degeneration was checked by Luxol fast blue (LFB) staining and the immunohistochemical staining of myelin basic protein (MBP) and myelin proteolipid (PLP). Cell apoptosis was measured by TUNEL. Microglia polarization was evaluated by Iba-1, CD86 and CD163 immunohistochemical staining in vivo. The SIM-A9 cells cultured were divided into CMC-Na group, DHTS1 group, CMC-Na combined with LPS group and DHTS1 combined with LPS group. The expression of CD16/32, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) was analyzed by flow cytometry in vitro. Results Compared with CMC-Na combined with cuprizone group, DHTS1 treatment significantly attenuated myelin loss and cell apoptosis, reduced the area of Iba-1+ amoebic microglia and the number of CD86+ cells, while increased the number of CD163+ cells in the corpus callosum area of the brain. In addition, compared with CMC-Na combined with LPS group, DHTS1 obviously decreased the percentages of CD16/32+, iNOS+, TNF-α+ microglia. Conclusion DHTS1 can suppress cuprizone-induced demyelination and cell apoptosis through regulating the microglia polarization and mitigating inflammatory reaction in the central nerve system.