Microglial dynamics and emerging therapeutic strategies in CNS homeostasis and pathology

Abstract

Microglia, the resident immune cells of the central nervous system (CNS), are highly dynamic and play critical roles in maintaining CNS homeostasis. Under normal conditions, microglia continuously monitor their environment, clear cellular debris, and regulate homeostasis. In response to disease or injury, however, they undergo rapid morphological and functional changes, often adopting an amoeboid shape that facilitates phagocytosis of abnormal cells, pathogens, and external antigens. Microglia also proliferate in areas of injury or pathology, contributing to immune responses and tissue remodeling. Recently, pharmacological approaches targeting microglial depletion and repopulation have gained attention as a means to reset or modulate microglial function. Techniques such as CSF1R inhibition enable transient depletion of microglia, followed by rapid repopulation, potentially restoring homeostatic functions and mitigating chronic inflammation. This review explores the current understanding of microglial dynamics and highlights emerging therapeutic applications of microglial depletion and repopulation within the CNS.

Keywords: CNS homeostasis; CSF1; CSF1R; microglia; microglia depletion; microglial dynamics; pathology; therapeutic strategies.

FIGURE 1

CSF-1R signaling pathways and the effects of CSF-1R inhibitors. Colony-stimulating factor 1 receptor (CSF-1R) is a shared receptor for both colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). Upon ligand binding, CSF-1R activates a cascade of downstream signaling pathways, including PI3K-AKT, ERK1/2, JAK/STAT, and NF-κB. These pathways regulate key cellular processes such as proliferation, survival, differentiation, and inflammatory responses, particularly within myeloid lineage cells. PLX5622, a selective small-molecule CSF-1R inhibitor, effectively blocks CSF-1R signaling, thereby suppressing the activation of these downstream pathways and reducing the survival and function of CSF-1R–dependent cells.

FIGURE 2

Microglial Depletion and Repopulation. Treatment with PLX5622, a CSF-1R inhibitor, leads to efficient depletion of microglia. Upon withdrawal of PLX5622, microglia undergo rapid repopulation, restoring their numbers and distribution within the central nervous system.