Moesin is involved in microglial activation accompanying morphological changes and reorganization of the actin cytoskeleton

Tomonori Okazaki,Kotoku Kawaguchi,Daichi Saito,Takashi Nakahari,Sayuri Wakimoto,Shinji Asano,Masatoshi Inden

doi:10.1186/s12576-020-00779-6

Tomonori Okazaki, Kotoku Kawaguchi + Show 5 more

Open Access

https://doi.org/10.1186/s12576-020-00779-6

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Abstract

Moesin is a member of the ezrin, radixin and moesin (ERM) proteins that are involved in the formation and/or maintenance of cortical actin organization through their cross-linking activity between actin filaments and proteins located on the plasma membranes as well as through regulation of small GTPase activities. Microglia, immune cells in the central nervous system, show dynamic reorganization of the actin cytoskeleton in their process elongation and retraction as well as phagocytosis and migration. In microglia, moesin is the predominant ERM protein. Here, we show that microglial activation after systemic lipopolysaccharide application is partly inhibited in moesin knockout (Msn-KO) mice. We prepared primary microglia from wild-type and Msn-KO mice, and studied them to compare their phenotypes accompanying morphological changes and reorganization of the actin cytoskeleton induced by UDP-stimulated phagocytosis and ADP-stimulated migration. The Msn-KO microglia showed higher phagocytotic activity in the absence of UDP, which was not further increased by the treatment with UDP. They also exhibited decreased ADP-stimulated migration activities compared with the wild-type microglia. However, the Msn-KO microglia retained their ability to secrete tumor necrosis factor α and nitric oxide in response to lipopolysaccharide.

Highlights

Microglia are immune cells resident in the central nervous system
We studied the roles of moesin in microglial morphology, phagocytosis, migration, and production and secretion of tumor necrosis factor α (TNF-α) and Nitric oxide (NO) in vitro by comparing the phenotypes of primary cultured microglia prepared from the WT and moesin knockout (Msn-KO) mice
We studied the microglial Ionized calcium-binding adapter molecule (Iba1) immunoreactivity in the substantia nigra pars compacta (SNpc), a brain region characterized by a relative high density of microglial cells [26, 27]

Summary

Introduction

Microglia are immune cells resident in the central nervous system. Under normal or resting conditions, microglia with numerous long and branched processes continuously survey their environment to identify abnormalities in surrounding cells. They retract their processes, induce hypertrophy of their cell bodies, and rapidly migrate toward the site of injury [1]. They secrete a number of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β, and cytotoxic molecules such as nitric. Microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers phagocytosis [5]. The activation of the purinergic P2Y6 receptor with UDP evokes microglia motility through the phosphorylation of Okazaki et al J Physiol Sci (2020) 70:52 an actin-binding vasodilator-stimulated phosphoprotein (VASP), which results in phagocytosis [6]. Microglia express the metabotropic P2Y12 and the ionotropic P 2X4 receptors whose activation by the endogenous agonist ATP triggers chemotaxis [7]. Rac GTPase, which may interact with ERM proteins, regulates a positive feedback loop between PI3K and actin polymerization [8]

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