巨噬细胞p50促进TGF-β1转录表达以诱导调节性T细胞控制血吸虫病肝脏免疫病理损害的机制研究

Schistosomiasis is one of the major human parasitic diseases worldwide. During schistosome infection significant immune suppression is induced in mammalian hosts, causing depressed immune responses against schistosomes, lower effciency of schistosome candidate vaccines and restriction of liver immunopathology in hosts. CD4+CD25+Foxp3+Treg cells remain the most prominent of immunoregulatory cells operating during helminth infections described to date. TGF-β is an essential factor for the conversion of CD4+CD25-T cells into CD4+CD25+Foxp3+Treg cells by inducing the key transcription factor Foxp3. However, the exact mechanism underlying the regulation of TGF-β1 expression remains unknown. This study intends to further explore the molecular mechanism of transcriptional activation of TGF-β1 by stimulation of macrophages through TLR4-Mal pathway with schistosome antigens. Our findings may be helpful to develop some new strategies to enhance the immune suppression to control the development of liver pathology during schistosome infection and/or improve the protection of the potential vaccine against Schistosoma japonicum.

血吸虫病是我国及全球危害最严重的寄生虫病之一。血吸虫可诱导宿主产生显著的免疫负调控，造成宿主抗感染免疫力、血吸虫病候选疫苗保护力均普遍低下，却可减轻和延缓宿主肝脏的进行性免疫病理损害（最主要致病因素，最终导致肝硬化及各种严重并发症甚至死亡）。迄今，Treg细胞被公认为是蠕虫感染中免疫负调控形成的最重要机制。TGF-β1是诱导关键转录因子Foxp3表达、从而使非Treg细胞转变为Treg细胞的必需细胞因子。但是，TGF-β1产生的确切分子机制至今不清。本项目拟在前期基础上，深入探索血吸虫抗原经TLR4-Mal信号在转录水平上促进TGF-β1表达、从而诱导Treg细胞的分子机制，进而加深对包括血吸虫在内的诸多病原体诱导宿主免疫负调控机制的认识，最终为提高流行区人群抗感染免疫力、疫苗研制及优化、干预临床肝脏免疫病理损害提供重要的理论和实践依据。

血吸虫病是我国及全球危害最严重的寄生虫病之一。血吸虫可诱导宿主产生显著的免疫负调控，造成宿主抗感染免疫力、血吸虫病候选疫苗保护力均普遍低下，却可减轻和延缓宿主肝脏的进行性免疫病理损害（最主要致病因素，最终导致肝硬化及各种严重并发症甚至死亡）。迄今，Treg细胞被公认为是蠕虫感染中免疫负调控形成的最重要机制。TGF-β1是诱导关键转录因子Foxp3表达、从而使非Treg细胞转变为Treg细胞的必需细胞因子。但是，TGF-β1产生的确切分子机制至今不清。因此，本研究首先发现，血吸虫抗原（SjHSP60）是通过TLR4-Mal信号途径诱导Mφ表达TGF-β1，从而诱导Treg 细胞并控制血吸虫感染小鼠的肝脏免疫病理损害；进一步研究发现SjHSP60可通过TLR4-Mal信号途径增加了IKKα，进而诱导了p50，从而在转录水平上激活TGF-β1启动子，从而促进其转录和表达。本研究加深了对包括血吸虫在内的诸多病原体诱导宿主免疫负调控机制的认识，最终为提高流行区人群抗感染免疫力、疫苗研制及优化、干预临床肝脏免疫病理损害提供重要的理论和实践依据。