PHF11通过NF-κB靶向NLRP3炎症体调控角质形成细胞固有免疫应答的作用和机制研究

Disorders of immune system result in psoriatic lesions. However, the molecular pathological mechanisms are still unclear. The dearth of clinically effective treatment options makes psoriatic lesions the least treatable form of skin diseases. NLRP3 inflammasome is an important component in innate immunity, and plays a key role in the development of many diseases. Regulation of expression of cytokines by NLRP3 inflammsome, expected bridge between innate and adaptive immune in keratinocytes. Nuclear factor kappa B (NF-κB) is a transcriptional factor. It is a key regulator of the inflammatory cascade in psoriatic lesions. And, NF-κB-dependent signals modulate the expression of NLRP3 and activation of NLRP3 inflammasome. A new study finds that PHF11 is capable of regulating innate immune responses in keratinocytes. We firstly indicate that PHF11 highly expresses in keratinocytes of psoriatic lesions, and mediated transcriptional activity of NF-κB and release of cytokines. Therefore, the present study aims to systematically investigate mechanisms of PHF11 on modulating innate immune responses of keratinocytes and inflammation in psoriatic lesions. Various techniques will be used, including in vivo and in vitro models, gene delivery, immunohistochemistry, EMSA and so on. The results will be conducive to understanding the occurrence and progress of inflammatory injury of psoriatic lesions. Taken together, the study will provide theoretical and experimental basis for designing and verifying new therapeutic strategies against inflammation of psoriatic lesions.

银屑病皮损与固有免疫和适应性免疫紊乱等因素有关，但其分子机理尚不明确，临床缺乏针对性治疗方案。NLRP3炎症体作为固有免疫重要组分在疾病发展中发挥关键作用。角质形成细胞中，NLRP3炎症体调节炎性因子释放，搭起银屑病皮损固有免疫和适应性免疫间的桥梁。核转录因子NF-κB是银屑病皮损炎性级联反应关键调节枢纽，在NLRP3表达和NLRP3炎症体活化中发挥重要作用。我们率先发现，一种调控角质形成细胞固有免疫应答的蛋白PHF11，在银屑病皮损区高表达，能够调控NF-κB转录活性和其介导的炎性反应。本项目拟利用体内、体外模型，结合基因调控、免疫组化和EMSA等技术，阐明PHF11通过NF-κB靶向NLRP3炎症体，调控角质形成细胞固有免疫应答和银屑病皮损炎性反应的作用机制。研究结果有望完善对银屑病皮损炎性反应发生发展核心过程的认识，为设计和验证银屑病皮损针对性治疗新策略提供理论基础和实验依据。

银屑病皮损与固有免疫和适应性免疫紊乱等因素有关，但其分子机理尚不明确，临床缺乏针对性治疗方案。作为免疫炎症反应最重要的调控因子之一，核因子κB（NF-κB）可以与 150 余种基因的启动子或增强子特异结合。角质形成细胞中，NF-κB调节炎性因子释放，搭起银屑病皮损固有免疫和适应性免疫间的桥梁，是银屑病皮损炎性级联反应关键调节枢纽。我们发现调控角质形成细胞固有免疫应答的蛋白PHF11，在银屑病皮损区高表达，能够调控NF-κB转录活性和其介导的炎性反应。本课题中，我们利用蛋白印迹、免疫组化、病毒转染等技术，阐明PHF110通过NF-κB调控角质形成细胞固有免疫应答和银屑病皮损炎性反应的作用机制。此外，我们还发现了其家族成员PHF20在银屑病发病机制中的重要作用，我们利用免疫组化检测了正常组织和银屑病皮损PHF20的表达变化情况，确立了PHF20蛋白在银屑病皮损中的高表达。在角质形成细胞中，通过基因沉默技术成功的阻断了PHF20表达后，咪喹莫特（imiquimod）诱导的NF-κB 活性降低，NF-κB 下游蛋白XIAP、A20的表达也显著减少，同时IL-8、IL-1b、IFN-a、CXCL1、CCL20的表达也相应的降低。我们的研究成果有望完善对银屑病皮损炎性反应发生发展核心过程的认识，为设计和验证银屑病皮损针对性治疗新策略提供理论基础和实验依据。