Pathophysiological role of microglia/macrophages in CNS demyelinating disease

[Speaker] Hisashi Shirakawa:1
1:Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

Central nervous system (CNS) inflammation involving various types of immune cells is a potential therapeutic target for CNS diseases. In recent years, a number of studies have focused on the pathophysiological roles of microglia, the most abundant CNS resident immune cells, and CNS-infiltrating macrophages, both of which can migrate toward sites of CNS tissue damage with inflammation. Whereas their roles in CNS inflammation are still under debate, their contribution to CNS diseases could be more manifested in CNS demyelinating diseases, in which focal inflammatory white matter injury are observed. Here we discuss the evidence that regulation of transient receptor potential (TRP) channels, a nonselective Ca2+-permeable cation channels that serve as cellular sensors for mechanical, thermal, and chemical stimuli, in microglia/macrophages can modulate CNS inflammation and subsequent white matter injury in CNS diseases. In particular, we focus on the pathophysiological role of TRPM2, a redox-sensitive cation channel. At first, we demonstrate that TRPM2 in CNS-infiltrating macrophages plays a crucial role in development of experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model for the common demyelinating disease multiple sclerosis. EAE progression was suppressed by gene knockout or pharmacological inhibition of TRPM2; this was attributed to a reduction in CXCL2 chemokine production by CNS-infiltrating macrophages in TRPM2-knockout mice, resulting in suppression of neutrophil infiltration into the CNS. These results reveal an important role of TRPM2 in the pathogenesis of EAE. Next, we used a chronic cerebral hypoperfusion mouse model to investigate the role of TRPM2, and found that TRPM2-mediated activation of microglia, not macrophages, specifically contributes to inflammatory responses, demyelination and cognitive impairment. Taken together, these findings shed light on the understanding of the mechanisms of CNS inflammation, and are expected to provide a novel therapeutic molecule in microglia/macrophages for CNS demyelinating diseases.
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