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Dihydroartemisinin Shows Promising Effects in the Treatment of Experimental Autoimmune Encephalomyelitis and Maintains Inflammatory Homeostasis by Targeting AXL in Microglia

Xiaoxin, Z;Qingsen, R;Li, Q;Li, L;Lidong, S;Qing, Y;Yujie, L;Ying, C;Xiaogang, W;Yajie, W;Weiyan, C;

Background: During EAE progression, the endogenous mechanisms mediating nervous autoimmune inflammation balance, as represented by AXL, were proved to be pathologically disturbed, immune balance and axon repair. Therapeutically, by activating AXL signaling, the inflammatory rebalance from promotion to resolution has attracted increasing attention and showed advantages in autoimmune disease treatment. Previous studies implied that DHA had potential effects in treating autoimmune diseases. However, the detailed mechanisms in inflammation regulation, especially in CNS, remain unclear.Methods: C57BL/6 mice were immunized with MOG35-55 and treated daily with DHA. Then clinical scores, pathology, and ethology features of EAE were assessed through histological staining (H&E, LFB staining), TEM and gait analysis. Moreover, DHA-responsive cells and genes were screened by 10x Genomics. The immunological responses to DHA were measured by flow cytometry and fluorescence microscope in BV2 cells. The concentrations and bio-activities of chemokines were respectively evaluated through ELISA and trans-well assay. Results: After DHA treatment, the clinical scores and body weight were significantly improved. Histologically, mice showed slighter spinal cord lesion, less inflammatory cuffs. By using gait analysis, DHA obviously improved physical coordination. 10x Genomics demonstrated that DHA selectively upregulated AXL expression in microglia. Immunologically, by enhancing AXL signaling, the phagocytic and chemotactic potential of microglia and the Treg differentiation followed by upregulating PDL1 were significantly influenced by DHA. Conversely, specific blocking of AXL by SGI7079 was sufficient to reverse above-mentioned functions. Molecularly, DHA specifically rebalanced the overactivated inflammation through STAT1:SOCS3: AXL: IFNAR pathway. Conclusions: The present study highlighted the central role of AXL signaling in DHA mediated inflammatory transition.