维甲酸诱导COX1的分子机制及其在宿主抗病毒免疫中的调控作用

The long term goal of this application is to elucidate the mechanisms and biological significance of the crosstalk between the innate immune response and nuclear hormone receptors in regulating viral infectious diseases. Nuclear receptor RXR (Retinoid X receptor) plays critical roles in numerous metabolic processes including drug metabolism and lipid metabolism. Type I IFN (IFN-I) is the key factor of host antiviral immunity. However, overproduction of IFN-I leads to autoimmune diseases such as systemic lupus erythematosus (SLE) and arthritis. Our previous study has shown that overexpression of RXR or ligand activation of RXR by retinoic acid suppresses IFN-I production and promotes viral infections, while down-regulation of RXR expression or antagonist inhibition of RXR enhances IFN-I-mediated host antiviral immunity. Our preliminary results of this proposal have indicated that retinoic acid may induce its downstream gene COX1, which is believed over 30 years as a constitutively expressed gene, and related COX1 product PGE2 to suppress IFN-I production and host antiviral immunity. The purpose of this proposal is to elucidate the molecular mechanisms responsible for RXR-mediated induction of COX1 and the role of the COX1 induction in regulating IFN-I expression. The studies of this proposal will describe the role of retinoic acid in maintaining homeostasis by inhibiting IFN-I during normal physiological condition and the recovery period after viral infection. In addition, we will also investigate the potential risk of the retinoids and rexinoids in viral infectious diseases.

本项目的长期目标是阐明在病毒感染性疾病中固有免疫与核受体介导的代谢过程如何相互调节。核受体RXR（Retinoid X receptor）在药物代谢等诸多代谢过程中起至关重要的作用。I型干扰素（IFN-I）在宿主抗病毒感染免疫过程中起决定性的用，然而过量的IFN-I会引起系统性红斑狼疮等自身免疫病。我们之前的研究表明：高表达RXR或维甲酸（RXR激动剂）处理能抑制宿主细胞产生IFN-I从而促进病毒感染。我们的预实验结果表明维甲酸可能通过诱导其下游基因COX1及其产物PGE2从而抑制IFN-I产生。本项目将阐明维甲酸诱导COX1基因的分子机制以及COX1基因在IFN-I产生和宿主抗病毒免疫反应中的调控作用，从而揭示内源性维甲酸在正常生理状况下及病毒感染后的恢复期起抑制过度IFN-I产生以及维持内稳态的作用，同时提示维甲酸类药物在病毒感染性疾病中潜在的风险。

本项目的长期目标是阐明在病毒感染性疾病中固有免疫与核受体介导的代谢过程如何相互调节。核受体RXR（Retinoid X receptor）在药物代谢等诸多代谢过程中起至关重要的作用。I型干扰素（IFN-I）在宿主抗病毒感染免疫过程中起决定性的用，然而过量的IFN-I会引起系统性红斑狼疮等自身免疫病。本项目之前的研究表明：高表达RXR或维甲酸（RXR激动剂）处理能抑制宿主细胞产生IFN-I从而促进病毒感染。通过本项目的研究证实维甲酸可能通过诱导其下游基因COX1及其产物PGE2从而抑制IFN-I产生。本项目阐明了维甲酸诱导COX1基因的分子机制以及COX1基因在IFN-I产生和宿主抗病毒免疫反应中的调控作用，揭示了内源性维甲酸在正常生理状况下及病毒感染后的恢复期起抑制过度IFN-I产生以及维持内稳态的作用，同时提示维甲酸类药物在病毒感染性疾病中潜在的风险。此外，我们还发现维甲酸诱导COX1的大量表达能显著促进NLRC4/NIAP5介导的炎症反应，引起“类花生四烯酸风暴”。