11月3日免疫學(xué)專業(yè)期刊《免疫學(xué)雜志》（Journal of Immunology）在線發(fā)表了中科院上海生科院生化與細(xì)胞所孫兵研究組最新研究論文,。
天然免疫反應(yīng)作為機(jī)體防御病原體的第一道防線，主要通過模式識(shí)別受體PRR來識(shí)別病原體編碼的病原相關(guān)分子模式PAMP,，其中Nod樣受體（NLR）是模式識(shí)別受體中非常重要的一類,。這些受體可以識(shí)別不同病原體的分子模式，通過信號(hào)轉(zhuǎn)導(dǎo)誘導(dǎo)許多免疫和炎癥基因的表達(dá),，從而使機(jī)體建立抵御外界病原體的先天免疫狀態(tài),。NLRP3作為NLR的一員,，在激活之后能夠通過與其接頭蛋白ASC相互作用，招募Pro-caspase-1,，形成蛋白復(fù)合物“炎癥小體”,，進(jìn)而對(duì)Pro-IL-1β等底物進(jìn)行切割使其成熟并釋放到胞外發(fā)揮功能。雖然研究發(fā)現(xiàn)許多病原體或體內(nèi)危險(xiǎn)信號(hào)都能激活NLRP3炎癥小體,，但是對(duì)于NLRP3炎癥小體的調(diào)控過程還不清楚,。
孫兵研究組在以前的研究中發(fā)現(xiàn)TRIM30能夠通過降解TLR信號(hào)通路中的重要分子TAB2/TAB3來負(fù)性調(diào)控TLR信號(hào)通路。在本研究中,，胡宇和毛開睿博士發(fā)現(xiàn)TRIM30也能夠負(fù)性調(diào)節(jié)NLRP3炎癥小體的激活,。在用各種刺激劑激活NLRP3炎癥小體的情況下，抑制TRIM30的表達(dá)能夠促進(jìn)caspase-1的活化進(jìn)而增強(qiáng)IL-1β的成熟和分泌,。同時(shí)他們還發(fā)現(xiàn)TRIM30可能是通過影響ROS的產(chǎn)生來調(diào)控NLRP3炎癥小體的激活,。在體內(nèi)，運(yùn)用MSU晶體誘導(dǎo)的小鼠腹腔炎模型也發(fā)現(xiàn),，在TRIM30轉(zhuǎn)基因小鼠體內(nèi)IL-1β的分泌和嗜中性粒細(xì)胞的浸潤(rùn)都明顯下降,。通過體內(nèi)外實(shí)驗(yàn)他們證明了TRIM30能夠負(fù)性調(diào)控NLRP3炎癥小體。
此項(xiàng)研究成果得到科技部,、國(guó)家自然科學(xué)基金的資金資助,。（生物谷Bioon.com）
生物谷推薦英文摘要：
The Journal of Immunology, 2010, doi:10.4049/jimmunol.1001099
Tripartite-Motif Protein 30 Negatively Regulates NLR Family, Pyrin Domain-Containing 3 Inflammasome Activation by Modulating Reactive Oxygen Species Production
Yu Hu,*,1 Kairui Mao,*,1 Yan Zeng, Shuzhen Chen,* Zhiyun Tao,* Chen Yang,* Shuhui Sun, Xiaodong Wu,* Guangxun Meng, and Bing Sun*,
*Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science and Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences; and Fudan University School of Medicine, Shanghai, China
The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is critical for caspase-1 activation and the proteolytic processing of pro–IL-1β. However, the mechanism that regulates NLRP3 inflammasome activation remains unclear. In this paper, we demonstrate that tripartite-motif protein 30 (TRIM30) negatively regulates NLRP3 inflammasome activation. After stimulation with ATP, an agonist of the NLRP3 inflammasome, knockdown of TRIM30 enhanced caspase-1 activation and increased production of IL-1β in both J774 cells and bone marrow-derived macrophages. Similarly with ATP, knockdown of TRIM30 increased caspase-1 activation and IL-1β production triggered by other NLRP3 inflammasome agonists, including nigericin, monosodium urate, and silica. Production of reactive oxygen species was increased in TRIM30 knockdown cells, and its increase was required for enhanced NLRP3 inflammasome activation, because antioxidant treatment blocked excess IL-1β production. Conversely, overexpression of TRIM30 attenuated reactive oxygen species production and NLRP3 inflammasome activation. Finally, in a crystal-induced NLRP3 inflammasome-dependent peritonitis model, monosodium urate-induced neutrophil flux and IL-1β production was reduced significantly in TRIM30 transgenic mice as compared with that in their nontransgenic littermates. Taken together, our results indicate that TRIM30 is a negative regulator of NLRP3 inflammasome activation and provide insights into the role of TRIM30 in maintaining inflammatory responses.
