烟酰胺 N-氧化物通过 Sirtuin-1/NF-κB 信号通路减轻 HSV-1 诱导的小胶质细胞炎症。

Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling.

机构信息

Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

Guangdong Province Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.

出版信息

Int J Mol Sci. 2022 Dec 16;23(24):16085. doi: 10.3390/ijms232416085.

DOI:10.3390/ijms232416085

PMID:36555725

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9784159/

Abstract

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1β, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.

摘要

单纯疱疹病毒 1 型（HSV-1）是一种典型的嗜神经病毒，可感染大脑并引起角膜炎、唇疱疹，偶尔还会引起急性单纯疱疹病毒性脑炎（HSE）。HSV-1 感染诱导的大量促炎细胞因子是中枢神经系统（CNS）神经毒性的重要原因。小胶质细胞作为 CNS 中的固有巨噬细胞，是抵御神经嗜性病毒感染的第一道防线。抑制过度激活的小胶质细胞中炎症细胞因子的过度产生，是治疗 HSE 的关键策略。在本研究中，我们研究了烟酰胺 N-氧化物（NAMO）对 HSV-1 诱导的小胶质细胞炎症和 HSE 的影响。我们发现 NAMO 可显著抑制 HSV-1 感染小胶质细胞诱导的细胞因子（如 IL-1β、IL-6 和 TNF-α）的产生。此外，NAMO 促进小胶质细胞从促炎 M1 型向抗炎 M2 型转化。更详细的研究表明，NAMO 增强了 Sirtuin-1 的表达及其去乙酰化酶的酶活性，进而使 p65 亚基去乙酰化，抑制 NF-κB 信号转导，从而减少炎症反应并改善 HSE 病理。因此，Sirtuin-1/NF-κB 轴可能是针对包括 HSE 在内的与 HSV-1 感染相关疾病的有希望的治疗靶点。