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Hypothyroidism Promotes Microglia M1 Polarization by Inhibiting BDNF-Promoted PI3K-Akt Signaling Pathway
Yuan Zhan1,2, Lang Lang3, Fen Wang3
1Department of Geriatric Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, zzhan192623@126.com.
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.
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.
Insights
Hypothyroidism promotes harmful microglia M1 polarization by reducing brain-derived neurotrophic factor (BDNF). Restoring BDNF levels via the PI3K-Akt pathway may offer a therapeutic strategy for related neurological disorders.
Area of Science:
- Neuroscience
- Endocrinology
- Immunology
Background:
- Hypothyroidism negatively impacts patients' quality of life through neurological disorders.
- The precise link between hypothyroidism and microglia function in neurodegeneration remains unclear.
Purpose of the Study:
- To investigate how hypothyroidism influences microglia polarization.
- To identify the regulatory mechanisms underlying hypothyroidism-induced changes in microglia function.
Main Methods:
- Constructed a mouse model of hypothyroidism using methimazole.
- Analyzed microglia M1 polarization biomarkers and pro-inflammatory cytokines.
- Utilized lipopolysaccharide (LPS)-treated BV2 cells to study microglia polarization factors.
- Employed global transcriptome sequencing (RNA-seq) to uncover regulatory pathways.
Main Results:
- Hypothyroidism increased M1 microglia polarization biomarkers and pro-inflammatory cytokines while decreasing BDNF, TrkB, and IL-10 in mice.
- LPS treatment in BV2 cells reduced BDNF, IL-10, and Arg1; BDNF overexpression reversed LPS-induced inflammation.
- BDNF overexpression modulated gene expression, particularly within the PI3K-Akt signaling pathway, identifying Myc, Gdnf, Thbs1, and Ccnd1 as key targets.
Conclusions:
- Hypothyroidism promotes microglia M1 polarization by inhibiting BDNF expression.
- BDNF inhibits microglia M1 polarization via the PI3K-Akt signaling pathway.
- Targeting the BDNF-PI3K-Akt axis presents a potential therapeutic strategy for hypothyroidism-associated neuroinflammation.
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