Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA.
Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA,
Neuroendocrinology. 2019;108(4):291-307. doi: 10.1159/000496754. Epub 2019 Jan 10.
The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens.
To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1-7.
GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1-7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away.
Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.
神经炎症如何影响下丘脑神经元功能尚不清楚。我们之前的研究表明，肥胖介导的慢性炎症通过降低促性腺激素释放激素（GnRH）神经元的棘突密度，导致生殖功能出现性别特异性损伤。神经炎症和随后 GnRH 神经元棘突密度的减少对雄性小鼠是特异的，而雌性的保护作用与卵巢雌激素无关。
为了研究神经炎症诱导的细胞因子是否可以直接调节 GnRH 基因表达，我们在此研究了雄性体内和 GnRH 表达细胞系 GT1-7 中的信号通路和机制。
GnRH 神经元表达细胞因子受体，慢性或急性神经炎症会抑制体内 GnRH 基因的表达。白血病抑制因子（LIF）特别抑制 GT1-7 细胞中的 GnRH 表达，而其他细胞因子则没有。LIF 处理后激活 STAT3 和 MAPK 通路，但只有 MAPK 通路（特别是 p38α）足以抑制 GnRH 基因。LIF 诱导 cFOS，通过增强子区域的-1,793 位点抑制 GnRH 基因。在体内，高脂饮食后，cFOS 在 GnRH 神经元和血管终器漏血脑屏障附近的神经元中被诱导，但在更远的神经元中没有被诱导。
我们的结果表明，神经炎症引起的 LIF 增加诱导 cFOS 并抑制 GnRH 基因。因此，除了 GnRH 神经元的突触变化外，神经炎症细胞因子还直接调节基因表达和生殖功能，神经元靶标特异性可能源于与有孔毛细血管的接近。
