Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province 230032, China.
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province 230032, China; First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui Province 230032, China.
Mol Immunol. 2024 Apr;168:1-9. doi: 10.1016/j.molimm.2024.02.003. Epub 2024 Feb 17.
Dysfunctional mutations in SAMHD1 cause Aicardi-Goutières Syndrome, an autoinflammatory encephalopathy with elevated interferon-α levels in the cerebrospinal fluid. Whether loss of function mutations in SAMHD1 trigger the expression of other cytokines apart from type I interferons in Aicardi-Goutières Syndrome is largely unclear. This study aimed to explore whether SAMHD1 dysfunction regulated the expression of IL-34, a key cytokine controlling the development and maintenance of microglia, in SH-SY5Y neural cells. We found that downregulation of SAMHD1 in SH-SY5Y cells resulted in the upregulation of IL-34 expression. The protein and mRNA levels of NF-κB p65, the transactivating subunit of a transcription factor NF-κB, were also upregulated in SAMHD1-knockdown SH-SY5Y cells. It was further found SAMHD1 knockdown in SH-SY5Y cells induced an upregulation of IL-34 expression through the canonical NF-κB-dependent pathway in which NF-κB p65, IKKα/β and the NF-κB inhibitor IκBα were phosphorylated. Moreover, knockdown of SAMHD1 in SH-SY5Y cells led to the translocation of NF-κB p65 into the nucleus and promoted NF-κB transcriptional activity. In conclusion, we found SAMHD1 dysfunction induced IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells. This finding could lay the foundation for exploring the role of IL-34-targeting microglia in the pathogenesis of Aicardi-Goutières Syndrome.
SAMHD1 功能失调突变导致 Aicardi-Goutières 综合征，这是一种伴有脑脊液中干扰素-α水平升高的自身炎症性脑病。SAMHD1 功能丧失突变是否会触发 Aicardi-Goutières 综合征中除 I 型干扰素以外的其他细胞因子的表达，在很大程度上尚不清楚。本研究旨在探讨 SAMHD1 功能障碍是否会调节 SH-SY5Y 神经细胞中白细胞介素 34（一种控制小胶质细胞发育和维持的关键细胞因子）的表达。我们发现，SH-SY5Y 细胞中 SAMHD1 的下调导致 IL-34 表达上调。SAMHD1 敲低的 SH-SY5Y 细胞中的 NF-κB p65（转录因子 NF-κB 的转激活亚单位）的蛋白和 mRNA 水平也上调。进一步发现，在 SH-SY5Y 细胞中敲低 SAMHD1 通过经典的 NF-κB 依赖性途径诱导 IL-34 表达上调，其中 NF-κB p65、IKKα/β 和 NF-κB 抑制剂 IκBα 被磷酸化。此外，SH-SY5Y 细胞中 SAMHD1 的敲低导致 NF-κB p65 易位到细胞核中，并促进 NF-κB 转录活性。总之，我们发现 SAMHD1 功能障碍通过神经元 SH-SY5Y 细胞中的 NF-κB p65 诱导 IL-34 表达。这一发现为探索靶向小胶质细胞的 IL-34 在 Aicardi-Goutières 综合征发病机制中的作用奠定了基础。
