TREM2 Regulates Heat Acclimation-Induced Microglial M2 Polarization Involving the PI3K-Akt Pathway Following EMF Exposure.

Gen-Lin He,Zhen Luo,Yuan Wang,Yu-Long Tan,Ping Li,Ju Yang,Peng Gao,Ze-Ze Wang,Ting-Ting Shen,Xue Luo,Xue-Sen Yang

doi:10.3389/fncel.2019.00591

Abstract

The function of triggering receptor expressed on myeloid cells-2 (TREM2) has been described within microglia with a beneficial activated phenotype. However, the role of TREM2 underlying microglial phenotypic alterations in the cross-tolerance protection of heat acclimation (HA) against the inflammatory stimuli electromagnetic field (EMF) exposure is less well known. Here, we investigated the TREM2-related signaling mechanism induced by HA in EMF-stimulated N9 microglial cells (N9 cells). We found that EMF exposure significantly increased the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α, IL-1β, and IL-6), and the expression of M1 markers (CD11b and CD86); meanwhile, decreased the levels of anti-inflammatory cytokines (IL-4 and IL-10) and the expression of M2 markers (CD206 and Arg1) in N9 cells. Clearly, HA treatment decreased the secretion of TNF-α, IL-1β and IL-6 and the expression of CD11b and CD86, and enhanced the production of IL-4 and IL-10 and the expression of CD206 and Arg1. Moreover, TREM2 esiRNA and selective inhibitor of PI3K clearly decreased anti-inflammatory cytokines production, M2 markers expression, and phosphorylation of PI3K and Akt following HA plus EMF stimulation. These results indicate that TREM2 and PI3K-Akt pathway are involved in the cross-tolerance protective effect of HA in microglial polarization towards the EMF exposure. This finding inspires future studies that aim to explore the non-drug approaches underlying EMF stimulation and other central nervous system (CNS) inflammatory diseases.

Highlights

Over the past few decades, scientific experiments have reported contradictory results regarding the potential effects of electromagnetic fields (EMFs) on the nervous system (D’Andrea et al, 2003)
Enzyme-Linked Immunosorbent Assay (ELISA) detection indicated that EMF exposure resulted in increased levels of tumor necrosis factor-α (TNF-α) (Figure 1A), IL-1β (Figure 1B), but not IL-6 (Figure 1C), and decreased levels of IL-4 (Figure 1D) and IL-10 (Figure 1E)
It was found that EMF exposure significantly increased the expression of cell surface marker CD11b and M1 marker CD86 (Figure 2A) and decreased the expression of CD206 and arginase 1 (Arg1) (Figure 2B), and these effects were reversed by Heat acclimation (HA) pre-conditioning

Summary

Introduction

Over the past few decades, scientific experiments have reported contradictory results regarding the potential effects of electromagnetic fields (EMFs) on the nervous system (D’Andrea et al, 2003). HA provides neuroprotection against a variety of stressors, including heatstroke (Yi et al, 2017), hyperoxia (Arieli et al, 2003), and traumatic brain injury (Shein et al, 2008). To date, these effects have not yet been studied in response to EMF exposure; similar beneficial roles are hypothesized. Post-experimental traumatic brain injury and, microglial immunoreactivity are enhanced upon the alleviation of injury in HA-treated mice (Shein et al, 2008). These results suggest that microglia may be involved in HA-induced neuroprotection

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Discussion

Conclusion