Zhan Yuan, Lang Lang, Wang Fen, Wu Xian, Zhang Haiwang, Dong Yuelin, Yang Hao, Zhu Defa
Department of Geriatric Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China,
Intensive Care Unit, The Second People's Hospital of Hefei, Hefei, China,
Neuroendocrinology. 2025;115(1):34-47. doi: 10.1159/000542858. Epub 2024 Dec 4.
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.
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.
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.
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.
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.
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.
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.
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.
甲状腺功能减退症及其引发的神经相关疾病极大地影响了患者的健康相关生活质量。同时，大脑中的小胶质细胞对神经退行性变具有重要的调节功能，但甲状腺功能减退症与小胶质细胞功能之间的潜在联系在很大程度上尚不明确。
我们通过构建甲巯咪唑诱导的小鼠模型并检测小胶质细胞M1极化生物标志物的表达模式，来解读甲状腺功能减退症如何调节小胶质细胞的极化。然后，我们使用脂多糖（LPS）处理的BV2细胞来探究影响小胶质细胞M1极化的因素。最后，利用全转录组测序（RNA测序）来确定潜在的调控机制。
我们检测到甲状腺功能减退症小鼠大脑中小胶质细胞M1极化生物标志物和促炎细胞因子显著增加；甲状腺功能减退症还会抑制脑源性神经营养因子（BDNF）和酪氨酸激酶受体B（TrkB）以及白细胞介素-10（IL-10）等抗炎细胞因子的表达。在BV2细胞中，LPS处理降低了BDNF、IL-10和精氨酸酶1（Arg1）的表达，而BDNF过表达（BDNF-OE）显著逆转了LPS诱导的炎症。BDNF-OE显著抑制诱导型一氧化氮合酶（iNOS）和肿瘤坏死因子-α（TNF-α）的表达，但增加了IL-10和Arg1的表达。关于机制，RNA测序分析表明BDNF-OE可通过影响基因表达全局调节转录组图谱。在LPS处理的BV2细胞中，BDNF-OE显著改变了参与磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路的基因表达模式，包括上调基因血小板反应蛋白3（Thbs3）、原癌基因Myc、胶质细胞源性神经营养因子（Gdnf）、血小板反应蛋白1（Thbs1）和细胞周期蛋白D1（Ccnd1），以及下调基因鸟嘌呤核苷酸结合蛋白β4（Gnb4）、成纤维细胞生长因子22（Fgf22）、磷脂酰肌醇-3激酶调节亚基3（Pik3r3）、胎盘生长因子（Pgf）、细胞周期蛋白依赖性激酶抑制因子1A（Cdkn1a）和血小板衍生生长因子受体α（Pdgfra）。Myc、Gdnf、Thbs1和Ccnd1在PI3K-Akt信号通路中的表达水平比其他基因高得多，可能是BDNF逆转小胶质细胞M1极化的有前景的靶点。
我们的研究得出了一个可靠的结论，即甲状腺功能减退症通过抑制大脑中BDNF的表达促进小胶质细胞M1极化；BDNF可通过激活PI3K-Akt信号通路抑制小胶质细胞的M1极化，这可能成为未来治疗小胶质细胞诱导的神经退行性或情感障碍的有前景的治疗靶点。
甲状腺功能减退症及其引发的神经相关疾病极大地影响了患者的健康相关生活质量。同时，大脑中的小胶质细胞对神经退行性变具有重要的调节功能，但甲状腺功能减退症与小胶质细胞功能之间的潜在联系在很大程度上尚不明确。
我们通过构建甲巯咪唑诱导的小鼠模型并检测小胶质细胞M1极化生物标志物的表达模式，来解读甲状腺功能减退症如何调节小胶质细胞的极化。然后，我们使用脂多糖（LPS）处理的BV2细胞来探究影响小胶质细胞M1极化的因素。最后，利用全转录组测序（RNA测序）来确定潜在的调控机制。
我们检测到甲状腺功能减退症小鼠大脑中小胶质细胞M1极化生物标志物和促炎细胞因子显著增加；甲状腺功能减退症还会抑制脑源性神经营养因子（BDNF）和酪氨酸激酶受体B（TrkB）以及白细胞介素-10（IL-10）等抗炎细胞因子的表达。在BV2细胞中，LPS处理降低了BDNF、IL-10和精氨酸酶1（Arg1）的表达，而BDNF过表达（BDNF-OE）显著逆转了LPS诱导的炎症。BDNF-OE显著抑制诱导型一氧化氮合酶（iNOS）和肿瘤坏死因子-α（TNF-α）的表达，但增加了IL-10和Arg1的表达。关于机制，RNA测序分析表明BDNF-OE可通过影响基因表达全局调节转录组图谱。在LPS处理的BV2细胞中，BDNF-OE显著改变了参与磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路的基因表达模式，包括上调基因血小板反应蛋白3（Thbs3）、原癌基因Myc、胶质细胞源性神经营养因子（Gdnf）、血小板反应蛋白1（Thbs1）和细胞周期蛋白D1（Ccnd1），以及下调基因鸟嘌呤核苷酸结合蛋白β4（Gnb4）、成纤维细胞生长因子22（Fgf22）、磷脂酰肌醇-3激酶调节亚基3（Pik3r3）、胎盘生长因子（Pgf）、细胞周期蛋白依赖性激酶抑制因子1A（Cdkn1a）和血小板衍生生长因子受体α（Pdgfra）。Myc、Gdnf、Thbs1和Ccnd1在PI
