Hypothyroidism Promotes Microglia M1 Polarization by Inhibiting BDNF-Promoted PI3K-Akt Signaling Pathway.

Introduction: Hypothyroidism and its induced neurological-associated disorders greatly affect the health-related quality of patients' life. Meanwhile, microglia in brain have essential regulatory functions on neurodegeneration, but the underlying link between hypothyroidism and microglia function is largely ambiguous.

Methods: We deciphered how hypothyroidism modulates the polarization of microglia by constructing methimazole-induced mice model and checking the expression pattern of biomarkers of microglia M1 polarization. Then, we used lipopolysaccharide (LPS)-treated BV2 cells to explore the effecting factors on microglia M1 polarization. Finally, global transcriptome sequencing (RNA-seq) was utilized to identify the underlying regulatory mechanisms.

Results: We detected that 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. BDNF-OE significantly repressed expression of iNOS and TNF-α, but increased expression of IL-10 and Arg1. For mechanism, RNA-seq analysis demonstrated that BDNF-OE could globally regulate transcriptome profile by affecting gene expression. In LPS-treated BV2 cells, BDNF-OE significantly altered expression pattern of genes involved in PI3K-Akt signaling pathway, including Thbs3, Myc, Gdnf, Thbs1, and Ccnd1 as upregulated genes, and Gnb4, Fgf22, Pik3r3, Pgf, Cdkn1a, and Pdgfra as downregulated genes. Myc, Gdnf, Thbs1, and Ccnd1 showed much higher expression levels than other genes in PI3K-Akt signaling pathway and could be promising targets of BDNF in reversing microglia M1 polarization.

Conclusion: Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF expression in brain; BDNF could inhibit the M1 polarization of microglia by activating PI3K-Akt signaling pathway, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future.