Molecular Mechanisms Determining Opposed Functional States of Microglia

Kazuyuki      Nakajima; Tadashi      Kurihara; Shinichi      Kohsaka

Abstract

Microglia are bone marrow-derived, monocyte-lineaged cells in the central nervous system (CNS). They are considered to serve as sensor cells, receiving a variety of alterations in the circumstances and responding with morphological and functional transformations. These responses of microglia in the injured or the pathologically damaged brain have been generally described as “microglial activation”. The main function of the activated microglia is to serve at the defense line of the CNS as brain macrophages / scavengers, and as immune or immunomodulator cells. Furthermore, microglia are supposed to regulate the survival, growth, and functions of neurons and other glial cells by producing a wide variety of physiologically active substances. They can actually produce both deleterious factors to induce neuronal cell death / degeneration and the trophic / protective molecules for neurons. The molecular mechanism by which the activated microglia are oriented in a harmful or a protective state was investigated by comparing both signal transduction molecules and the secretion of harmful and trophic molecules. As a result, p38MAPK activation was proved to be crucial for the induction of harmful factors, and PKC activity to be additionally required for the harmful state. In conclusion, the signal transduction pathway including p38MAPK activation linked to PKC activity is required for the induction of deleterious factors in microglia.

Keywords: microglia, toxic function, harmful factors, trophic function, neurotrophic molecules, signal transduction, central nervous system

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