ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway
ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway
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ROR α 通过下调 SIRT1/NF-kappa B 通路来预防 LPS 诱导的炎症
DOI：
10.1016/j.abb.2019.05.003
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发表时间：
2019-06-15
影响因子：
3.9
通讯作者：
Hu, Dahai
中科院分区：
文献类型：
--
作者：
Han, Shichao;Li, Zhenzhen;Hu, Dahai
全身炎症反应综合征（SIRS）与过度的炎症反应有关，然而，炎症的病理生理机制知之甚少。类维生素A相关孤儿受体α（ROR α）是一种关键的炎症调节因子，但其作用机制尚不清楚。本研究的目的是研究ROR α如何参与炎症反应的调节。本文提出了ROR α可能通过控制沉默信息调节因子Sirtuin 1（SIRT 1）的表达来负性调节炎症反应的假说。采用LPS体外刺激巨噬细胞和LPS体内给药的方法，探讨ROR α的功能以及ROR α与SIRT 1的关系。我们发现，在用LPS刺激的巨噬细胞中ROR α的水平被抑制，并且通过用慢病毒或siRNA转染ROR α的过表达或敲低分别显著降低或增加促炎细胞因子IL-1 β、TNF、IL-6和MCP-1。重要的是，ROR α的过表达抑制炎症并减轻体内LPS诱导的器官损伤。进一步的研究表明，ROR α可以调节SIRT 1的表达，从而影响核因子-κ B（NF-κ B）亚单位p65的去乙酰化和核转位。此外，SIRT 1的特异性激动剂SR 1720激活SIRT 1，可以减少LPS刺激的ROR α敲低巨噬细胞中促炎细胞因子的表达。总之，我们证明ROR α可以通过抑制NF-κ B p65核转位和限制NF-κ B p65在赖氨酸310处的乙酰化来减轻体内和体外LPS诱导的炎症和器官损伤。靶向ROR α可能是调节炎症性疾病的有希望的治疗策略。
Systemic inflammatory response syndrome (SIRS) is associated with excessive inflammatory response, however, the pathophysiology of inflammation is poorly understood. The retinoid-related orphan receptor alpha (ROR alpha) is a key inflammatory regulator, but the mechanisms underlying its role remain unclear. The aim of this study was to investigate how ROR alpha was involved in the regulation of inflammatory response. Here we put forward a hypothesis that ROR alpha might negatively regulate inflammatory response by controlling silent information regulator Sirtuin 1 (SIRT1) expression. Stimulation of macrophages in vitro with LPS and LPS administration in vivo were used to explore the function of ROR alpha and the relationship between ROR alpha and SIRT1. We found that the level of ROR alpha was suppressed in macrophages stimulated with LPS and overexpression or knockdown of ROR alpha by transfection with lentivirus or siRNAs significantly decreased or increased, respectively, the pro-inflammatory cytokines IL-1 beta, TNF, IL-6 and MCP-1. Importantly, overexpression of ROR alpha suppressed inflammation and alleviated LPS-induced organ injury in vivo. Further study showed that ROR alpha could regulate SIRT1 expression and, consequently, affect deacetyation and nuclear translocation of nuclear factor-kappa B (NF-kappa B) subunit p65. Moreover, the activation of SIRT1 by its specific agonist, SR1720, could reduce the expression of pro-inflammatory cytokines in ROR alpha knockdown macrophages stimulated with LPS. In conclusion, we demonstrated that ROR alpha could alleviate LPS-induced inflammation and organ injury both in vivo and in vitro by blocking NF-kappa B p65 nuclear translocation and restricting acetylation of NF-kappa B p65 at lysine 310 via the regulation of SIRT1 expression. Targeting ROR alpha might be a promising therapeutic strategy to regulate inflammatory disorders.