Roles of microglia on the development of neurological disorders

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The purpose of the study is to approach the mechanisms of intractable neurological disorders by analyzing the functions of microglia. The summary of our findings is as follows,1) Microglia derived from M-CSF deficient op/op mouse (type II microglia) did not produce either TNF, NO, IL-12 p70 or IL-18, while microglia derived from wild type (mainly type I microglia) produced all of them. This suggests that there may be different subtypes of microglia which have distinct functions. Since microglia-derived TNF or NO is considered to play critical roles on the development of neuronal degeneration or demyelination, two populations of microglia may have different roles on the pathophysiology of above conditions.2) In order to suppress TNF or NO production by microglia for future treatment, we examined the effects of phosphodiesterase inhibitors (PDEI) on TNF and NO production by microglia. PDEI suppressed TNF and NO production by microglia, also suppressed infection of murine AIDS virus in vitro. PDEI also suppressed the development of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Different types of PDEI functioned synergistically. Thus, the combination therapy of 2 to 3 different PDEI may be useful for future treatment of neurological disorders in which TNF or NO is involved in the pathophysiology.3) IL-13 with other stimulation for microglial proliferation induced multinucleated giant cell(MGC). MGC is observed in HIIV encephalopathy or CNS involvement of tuberculosis. The findings suggest the type 2 helper T cell-derived cytokines may be involved in the mechanisms of multinucleated giant cell formation.To study the function of microglia and its modification may provide us useful information for the strategy to treat intractable neurological disorders.