Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology

Abstract

Chemotactic cytokines (chemokines) have been traditionally defined as small (10-14kDa) secreted leukocyte chemoattractants. However, chemokines and their cognate receptors are constitutively expressed in the central nervous system (CNS) where immune activities are under stringent control. Why and how the CNS uses the chemokine system to carry out its complex physiological functions has intrigued neurobiologists. Here, we focus on chemokine CXCL12 and its receptor CXCR4 that have been widely characterized in peripheral tissues and delineate their main functions in the CNS. Extensive evidence supports CXCL12 as a key regulator for early development of the CNS. CXCR4 signaling is required for the migration of neuronal precursors, axon guidance/pathfinding and maintenance of neural progenitor cells (NPCs). In the mature CNS, CXCL12 modulates neurotransmission, neurotoxicity and neuroglial interactions. Thus, chemokines represent an inherent system that helps establish and maintain CNS homeostasis. In addition, growing evidence implicates altered expression of CXCL12 and CXCR4 in the pathogenesis of CNS disorders such as HIV-associated encephalopathy, brain tumor, stroke and multiple sclerosis (MS), making them the plausible targets for future pharmacological intervention.

Fig. 1. CXCL12/CXCR4 signaling pathways and their regulation

Binding of CXCL12 to CXCR4 activates multiple G-protein-mediated signaling pathways (such as PI3K, MAPKs and NFκB) and induces the release of intracellular Ca²⁺. These signaling pathways are involved in cell proliferation, migration and survival or apoptosis. Activation of CXCR4 leads to GRK/β-arrestin-mediated receptor desensitization and prevents CXCR4 from further interacting with G proteins. GRK/β-arrestin promotes clathin-dependent endocytosis that is coupled to receptor trafficking, degradation and resensitization. β-arrestin2 may modulate CXCR4-mediated activation of p38 MAPK signaling pathway.

Fig. 2

Roles of CXCL12/CXCR4 in brain development. The cartoon shows a schematic view of developing mouse brain (E12.5 and E15). CXCL12/CXCR4 regulates the migration of neuronal precursors during early brain development. (A) At embryonic day 12.5 (E12.5), CXCR4+ Cajal-Retzius (CR) cells are generated from the ventricular zone (VZ) near the lateral ventricle (LV) of the telencephalon and migrate to the marginal zone (MZ) through short range radial migration (blue arrow). CXCR4+ CR cells further spread to the whole telencephalon through long range tangential migration (yellow arrow). CXCL12 secreted from the meninges (dashed red line) is required for the migration of CR cells; (B) In E15 hippocampus, CXCR4+ dentate precursors are generated from subventricular zone (SVZ) near the lateral ventricle (LV). CXCL12 secreted from the meninges (dashed red line) guides the migration (blue line) of dentate precursors to the dentate gyrus (DG); (C) In E15 cerebellum, CXCR4+ granule cell precursors that are generated from the subventricular zone (SVZ) of rhombic lip (RL) migrate tangentially (yellow arrow) to cover most of the cerebellar surface forming the external granule cell layer (EGL). CXCL12 (dashed red line) secreted from meninges maintains cell proliferation and prevents premature exit of granular cell precursors from the EGL.