Hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-promoted PI3K-Akt signaling pathway

Hypothyroidism greatly affects the health­related quality of patients’ life, and microglia in brain have essential functions on neurodegeneration, but the underlying link between hypothyroidism and microglia function is largely ambiguous. Methods: Methimazole-induced mice was used to construct hypothyroidism model and explore the polarization of microglia. Lipopolysaccharide (LPS)-treated BV2 cells were used to investigate the effecting factors on microglia M1 polarization. Finally, global transcriptome sequencing (RNA-seq) was utilized to identify the underlying regulatory mechanisms. Results: The biomarkers of microglia M1 polarization and pro-inflammatory cytokines were significantly increased in hypothyroidism mice brain; hypothyroidism could also repress the expression of BDNF and TrkB, and the anti-inflammatory cytokine such as IL-10. In BV2 cells, LPS treatment decreased expression of BDNF, IL-10, and Arg1, while BDNF overexpression (BDNF-OE) significantly reversed the inflammation-induced by LPS by repressing iNOS and TNF-α, while increasing IL-10 and Arg1. RNA-seq analysis demonstrated that in LPS-treated BV2 cells, BDNF-OE significantly altered expression pattern of genes involved in PI3K-Akt signaling pathway, including the upregulated Thbs3, Myc, Gdnf, Thbs1, and Ccnd1, and the downregulated Gnb4, Fgf22, Pik3r3, Pgf, Cdkn1a, and Pdgfra. Myc, Gdnf, Thbs1, and Ccnd1 showed much higher expression levels than other genes in PI3K-Akt signaling pathway. Conclusions: Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-activated PI3K-Akt signaling pathway in brain, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future.