Microglial and macrophage polarization—new prospects for brain repair

Abstract

The traditional view of the adult brain as a static organ has changed in the past three decades, with the emergence of evidence that it remains plastic and has some regenerative capacity after injury. In the injured brain, microglia and macrophages clear cellular debris and orchestrate neuronal restorative processes. However, activation of these cells can also hinder CNS repair and expand tissue damage. Polarization of macrophage populations toward different phenotypes at different stages of injury might account for this dual role. This Perspectives article highlights the specific roles of polarized microglial and macrophage populations in CNS repair after acute injury, and argues that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes. Breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.

Figure 1. Polarized microglia/macrophages play distinct roles in restoration of the neurovascular network after stroke and other CNS injuries

Microglia/macrophages polarize toward M1 or M2 phenotypes at various stages of stroke and other CNS injuries. M1 microglia/macrophages, characterized by the expression of M1 signatures genes (eg. TNFα, iNOS and IL-6), release pro-inflammatory factors and free radicals that impair brain repair/regeneration. In contrast, M2 microglia/macrophages, characterized by the expression of M2 signatures genes (eg. Arg, CD206 and IL-10), improve brain repair/regeneration by enhancing phagocytosis, releasing tropic factors, and resolving cerebral inflammation. Arg: arginase; IL: interleukin; IL-1Ra: IL-1 receptor antagonist; iNOS: inducible nitric oxide synthase; MHCII: major histocompatibility complex II; TGF-β, transforming growth factor-β; TNFα: tumor necrosis factor-α.

Figure 2. Extracellular signals and intracellular molecular switches that control microglia/macrophage phenotypic changes

Recent studies have identified several intrinsic molecular switches that control phenotypic changes in microglia/macrophages. Targeting these molecular switches may lead to novel therapies that boost the repair function of microglia/macrophages and promote neurovascular network restoration after stroke and other CNS injuries. C/EBP-β: CCAAT-enhancer-binding protein-β; CREB: cyclic AMP response element binding protein; Irf: interferon response factor; miRNA: microRNA; PPAR-γ: peroxisome proliferator-activated receptor gamma-γ; STAT: signal transducer and activator of transcription.