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Review
. 2022 Feb 16:14:815347.
doi: 10.3389/fnagi.2022.815347. eCollection 2022.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

Shenrui Guo  1 , Hui Wang  1 , Yafu Yin  1
Affiliations
Review

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

Shenrui Guo et al. Front Aging Neurosci. .

Abstract

Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there's a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; microglia polarization; neurodegenerative diseases; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Important signal pathways in the modulation of microglia polarization. Activated TLR4 associates with MyD88 to induce the autophosphorylation of IRAK, which interacts with TRAF6. TRAF6 then activates the TAK1, activating two major pro-inflammatory pathways, IKK/IκB/NF-κB and MAPK (including ERK, JNK, p38)/AP-1 signaling pathways, thus the pro-inflammatory genes transcribe. Activated JAK induces the phosphorylation of STAT, and STAT1&STAT3 induce expression of pro-inflammatory mediators and negative feedback regulator SOCS. While STAT6 is involved in microglial M2 polarization. Calcium/CaMKKβ/AMPK signaling pathway is activated by Ca2+/CaM or LKB1, the latter is activated by increased AMP/ATP ratio. AMPK activates Sirt1, leading to the activation of PGC-1α, while AMPK also phosphorylates PGC-1α directly. PGC-1α interacts with PPAR-γ, which is involved in IL-4-induced M2 polarization. PPAR-γ antagonizes AP-1, NF-κB, and STAT1. GPCR and phosphorylated JAK could activate PI3K/AKT pathway. AKT prevents AMPK activation, and ERK and AKT inhibit each other.
FIGURE 2
FIGURE 2
Signal pathways activated for microglia polarization from M1 to M2 in different neurodegenerative diseases.
See this image and copyright information in PMC

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