TXNIP诱导Th9细胞活化在慢性鼻-鼻窦炎发病中的作用及机制研究

Chronic rhinosinusitis(CRS) is a common chronic inflammatory disease of the upper respiratory tract, and signal transduction pathway disorder of inflammatory cytokines, dis-regulation of innate immunity and T helper cells were involved in the pathogenesis of CRS. It has been shown that TXNIP was involved in the process of regulating cell metabolism, mediating oxidative stress and activating T lymphocytes. TXNIP was able to activate NLRP3 inflammasome and then induce the release of IL-1β and IL-18 to promote the generation and development of inflammation. Our earlier work demonstrated that NLRP3 inflammasome and IL-9/IL-9R relevant to Th9 cell play pivotal roles in the pathogenesis of CRS. Our pre-experiment showed that TXNIP was elevated in the nasal mucosa of CRS as compared with control group. In this study, we would further investigate the role and mechanism of TXNIP on Th9 cells activation in the pathogenesis of CRS. We speculate that TXNIP may activate NLRP3 inflammasome, enhance the transcription of IRF4 and PU-1, leading to the activation of Th9 cells and secretion of inflammatory cytokines, and sequentially facilitating the generation and development of CRS. This project would will be of great importance in illustrating deeply the pathogenesis of chronic rhinosinusitis and exploring gene therapy method.

慢性鼻-鼻窦炎（chronic rhinosinusitis, CRS）是常见的上呼吸道慢性炎症性疾病，CRS发病中存在炎症因子信号转导失调、先天性免疫及T辅助细胞免疫调控紊乱。既往研究发现，TXNIP具有调节细胞代谢、介导氧化应激反应及T淋巴细胞活化等功能，TXNIP可以激活NLRP3炎症小体，诱导下游IL-1β和IL-18的活化释放，促进炎症发生发展。我们前期工作发现NLRP3炎症小体与Th9细胞相关IL-9/IL-9R在CRS炎性发病过程中具有重要作用。预实验发现：与对照组比较，TXNIP在CRS鼻黏膜组织中表达明显升高。本项目将进一步深入研究TXNIP诱导Th9细胞活化在CRS中的作用及机制，设想TXNIP可激活NLRP3炎症小体，增强IRF4和PU-1转录，活化Th9细胞，促进炎症因子分泌，从而促进CRS发生发展。这些研究对深入阐明CRS发病机制及探索基因治疗具有重要意义。

慢性鼻窦炎（chronic rhinosinusitis, CRS）是常见的上呼吸道慢性炎症性疾病，研究发现氧化应激在CRS发病进程中起到重要作用。TXNIP可介导细胞氧化应激反应，且在ROS的作用下，TXNIP可激活NLRP3炎症小体，诱导下游IL-1β和IL-18的活化释放，促进炎症发生发展。我们的研究发现，TXNIP上调可通过降低TRX表达和SOD活性，促进CRSwNP中MDA的活性和ROS水平，进而提高氧化应激水平。通过进一步构建Type 2炎症反应小鼠模型，我们发现白藜芦醇可通过抑制TXNIP氧化应激通路对Type 2炎症反应小鼠产生抗炎作用；而选择性NLRP3抑制剂MCC950可通过抑制NLRP3炎症小体，使Caspase-1、Asc、IL-1β和IL-18水平降低，从而减轻小鼠炎症反应。基于以上研究结果，我们后续有望进一步探索针对TXNIP靶点，对CRSwNP进行基因治疗的相关研究，以期能够实现临床转化应用，从而减轻患者症状、减少社会经济负担。