Protective Microglia and Their Regulation in Parkinson's Disease

Abstract

Microglia-mediated neuroinflammation is a hallmark of Parkinson's disease (PD). In the brains of patients with PD, microglia have both neurotoxic and neuroprotective effects, depending on their activation state. In this review, we focus on recent research demonstrating the neuroprotective role of microglia in PD. Accumulating evidence indicates that the protective mechanisms of microglia may result from their regulation of transrepression pathways via nuclear receptors, anti-inflammatory responses, neuron-microglia crosstalk, histone modification, and microRNA regulation. All of these mechanisms work together to suppress the production of neurotoxic inflammatory components. However, during the progression of PD, the detrimental effects of inflammation overpower the protective actions of microglia. Therefore, an in-depth exploration of the mechanisms underlying microglial neuroprotection, and a means of promoting the transformation of microglia to the protective phenotype, are urgently needed for the treatment of PD.

Keywords: Parkinson’s disease; alternative activation; anti-inflammation; histone modification; microRNA; neuroinflammation; transrepression pathway.

FIGURE 1

Protective mechanisms of microglia in PD. (1) Anti-inflammatory action induced by cytokines (e.g., IL-4, IL-10, IL-13 and TGF-β). (2) Transrepression pathways through multiple nuclear receptors (e.g., GRs, PPARs, ERs, and Nurr1). (3) Neuron–microglia crosstalk (CD200–CD200R and CX3CL1–CX3CR1). (4) Histone modification (e.g., JMJD3). (5) MicroRNA regulation (e.g., miR-124). These protective mechanisms coordinate with each other to render microglia immunosuppressive or quiescent by inhibiting neurotoxic inflammatory components including reactive oxygen species, nitric oxide (NO), superoxide, various pro-inflammatory cytokines, and NF-κB and its downstream targets.