The roles of microglia and astrocytes in myelin phagocytosis in the central nervous system

Abstract

Myelination is an important process in the central nervous system (CNS). Oligodendrocytes (OLs) extend multiple layers to densely sheath on axons, composing the myelin to achieve efficient electrical signal conduction. The myelination during developmental stage maintains a balanced state. However, numerous CNS diseases including neurodegenerative and cerebrovascular diseases cause demyelination and disrupt the homeostasis, resulting in inflammation and white matter deficits. Effective clearance of myelin debris is needed in the region of demyelination, which is a key step for remyelination and tissue regeneration. Microglia and astrocytes are the major resident phagocytic cells in the brain, which may play different or collaborative roles in myelination. Microglia and astrocytes participate in developmental myelination through engulfing excessive unneeded myelin. They are also involved in the clearance of degenerated myelin debris for accelerating remyelination, or engulfing healthy myelin sheath for inhibiting remyelination. This review focuses on the roles of microglia and astrocytes in phagocytosing myelin in the developmental brain and diseased brain. In addition, the interaction between microglia and astrocytes to mediate myelin engulfment is also summarized.

Keywords: Astrocyte; brain; microglia; myelin engulfment; myelination.

Figure 1.

Processes involved in microglia and astrocytes-mediated phagocytosis. Phagocytic microglia and astrocytes recognize the molecules secreted by targeted cells, including ATP, UTP and fractalkine (“find me” signals). Then, the receptors in the membrane of microglia and astrocytes contact with the ligands (“eat me” signals), driving the engulfment of targeted cells and engulfed cells were delivered into the phagosome. Finally, the phagosome becomes mature, and the targeted cells are degraded in the phagolysosome within an acid environment (PH < 5).

Figure 2.

Microglia and astrocytes phagocytose myelin in the developmental brain. Myelinating OLs are derived from the proliferation, migration and differentiation of OPCs. Matured OLs generate lipidic myelin sheath. The excessive myelin needs to be cleared timely by phagocytic cells. Microglia phagocytose myelin through the receptors of LRP, TREM2, MERTK, CR3, etc. Astrocytes mediate myelin engulfment via LRP, MEGF10, etc.

Figure 3.

Myelin phagocytosis of microglia and astrocytes in CNS diseases. In diseased brain, microglia and astrocytes are activated and become phagocytic phenotypes. Myelin phagocytosis brings two side effects. On one hand, the normal engulfment of myelin debris will attenuate inflammation and be beneficial to remyelination. On the other hand, the abnormal or insufficient engulfment will trigger severe inflammation or even cell death and inhibit remyelination.

Figure 4.

Interaction of microglia and astrocytes in myelin phagocytosis in CNS diseases. After CNS injury, it will produce myelin debris causing tissue damage. Astrocytes could recruit microglia to clear myelin debris for further remyelination through CXCL10. Moreover, the secreted IL-6 by astrocytes could inhibit the production of microglial attracting chemokine CXCL10, CXCL1 and CCL4, and the phagocytosis associated receptor TREM2.