The inflammation and demyelination of the central nervous system (CNS) are mainly involved in multiple sclerosis (MS), in which the disorder of myelin regeneration leads to continual neurologic impairment. Fasudil, one of the ROCK inhibitors, has been shown protective functions in some models of demyelinating diseases. In this study, Fasudil treatment ameliorated the behavioral performance and myelin loss in CPZ-fed mice. Here, we demonstrated a new role of Fasudil, which triggered microglia to

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... uptake myelin debris in both cell and animal experiments. This increased phagocytosis was associated with the polarization of M2 microglia. Furthermore, we found that Fasudil enhanced the expression of triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), which regulated microglial phagocytosis and M2 polarization. The silence of TREM2 effectively blocked Fasudil-triggered phagocytic capacity, suggesting that Fasudil-triggered phagocytosis depends on TREM2 signaling pathway. Based on these evidences that TREM2 regulates microglial M2 polarization and phagocytosis, future studies targeted Fasudil as a therapy for demyelinating and neurodegenerative diseases are warranted.