Immunoproteasomal Processing of IsoLG-Adducted Proteins Is Essential for Hypertension
Circulation Research ( IF 16.5 ) Pub Date : 2024-04-16 , DOI: 10.1161/circresaha.124.324068
Néstor de la Visitación 1 , Wei Chen 1 , Jaya Krishnan 1 , Justin P Van Beusecum 1, 2, 3 , Venkataraman Amarnath 1 , Elizabeth M Hennen 4 , Shilin Zhao 5 , Mohammad Saleem 1 , Mingfang Ao 1 , Sergey I Dikalov 1 , Anna E Dikalova 1 , David G Harrison 1, 6 , David M Patrick 1, 6, 7

BACKGROUND:Hypertension is characterized by CD8+ T cell activation and infiltration into peripheral tissues. CD8+ T cell activation requires proteasomal processing of antigenic proteins. It has become clear that isoLG (isolevuglandin)-adduced peptides are antigenic in hypertension; however, IsoLGs inhibit the constitutive proteasome. We hypothesized that immunoproteasomal processing of isoLG-adducts is essential for CD8+ T cell activation and inflammation in hypertension.METHODS:IsoLG adduct processing was studied in murine dendritic cells (DCs), endothelial cells (ECs), and B8 fibroblasts. The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). We also examined hypertension in mice lacking the critical immunoproteasome subunit LMP7 specifically in either DCs or ECs.RESULTS:We found that oxidant stress increases the presence of isoLG adducts within MHC-I (class I major histocompatibility complex), and immunoproteasome overexpression augments this. Pharmacological or genetic inhibition of the immunoproteasome attenuated hypertension and tissue inflammation. Conditional deletion of LMP7 in either DCs or ECs attenuated hypertension and vascular inflammation. Finally, we defined the role of the innate immune receptors stimulator of interferon genes and TLR7/8 (toll-like receptor 7/8) as drivers of LMP7 expression in ECs.CONCLUSIONS:These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues.

中文翻譯：

IsoLG 加合蛋白的免疫蛋白酶體加工對于高血壓至關(guān)重要

背景：高血壓的特點(diǎn)是CD8 + T細(xì)胞活化并浸潤到外周組織。 CD8 + T 細(xì)胞的激活需要抗原蛋白的蛋白酶體加工。現(xiàn)已明確，isoLG（異左旋糖苷）誘導(dǎo)肽在高血壓中具有抗原性；然而，IsoLG 會(huì)抑制組成型蛋白酶體。我們假設(shè) isoLG 加合物的免疫蛋白酶體加工對于 CD8 + T 細(xì)胞激活和高血壓炎癥至關(guān)重要。方法：在鼠樹突狀細(xì)胞 (DC)、內(nèi)皮細(xì)胞 (EC) 和 B8 成纖維細(xì)胞中研究 IsoLG 加合物加工。在用硼替佐米或免疫蛋白酶體抑制劑 PR957 治療的C57BL/6小鼠中，并通過研究缺乏 3 個(gè)關(guān)鍵免疫蛋白酶體亞基的小鼠（三重敲除小鼠），研究了蛋白酶體和免疫蛋白酶體在 Ang II（血管緊張素 II）誘導(dǎo)的高血壓中的作用。我們還檢查了缺乏關(guān)鍵免疫蛋白酶體亞基 LMP7 的小鼠的高血壓情況，特別是在 DC 或 EC 中。結(jié)果：我們發(fā)現(xiàn)氧化應(yīng)激增加了 MHC-I（I 類主要組織相容性復(fù)合物）內(nèi) isoLG 加合物的存在，而免疫蛋白酶體過度表達(dá)則增強(qiáng)了這種情況。免疫蛋白酶體的藥理學(xué)或遺傳抑制可減輕高血壓和組織炎癥。 DC 或 EC 中 LMP7 的條件性缺失可減輕高血壓和血管炎癥。最后，我們定義了干擾素基因的先天免疫受體刺激劑和 TLR7/8（Toll 樣受體 7/8）作為 EC 中 LMP7 表達(dá)驅(qū)動(dòng)因素的作用。結(jié)論：這些研究定義了免疫蛋白酶體在 DC 中以前未知的作用和 ECs 在 CD8 + T 細(xì)胞激活中的作用。 DC 和 EC 中的免疫蛋白酶體對于將 isoLG 加合物呈遞給 CD8 + T 細(xì)胞至關(guān)重要，而在內(nèi)皮中，它引導(dǎo) T 細(xì)胞歸巢和浸潤到特定組織。

更新日期：2024-04-17

相關(guān)知識(shí)

Improvement Strategies for Dietary Energy Supply of Racehorses
食用植物油加工VOCs排放特征
電火花加工技術(shù)簡介.docx
古典美還是表現(xiàn)美：擺盤美學(xué)影響健康飲食決策的計(jì)算與神經(jīng)機(jī)制
The Health Benefits of Dietary Fibre
結(jié)構(gòu)健康監(jiān)測的傳感器優(yōu)化布置研究進(jìn)展與展望
黑木耳紅棗復(fù)合飲料工藝的研究
創(chuàng)傷后應(yīng)激障礙的網(wǎng)絡(luò)化心理干預(yù)及起效機(jī)制
西南交通大學(xué) 信息科學(xué)與技術(shù)學(xué)院
天津大學(xué)機(jī)械工程學(xué)院

網(wǎng)址: Immunoproteasomal Processing of IsoLG http://m.u1s5d6.cn/newsview884282.html