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Immunoproteasomal Processing of IsoLG

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2024-12-28 21:05

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.

中文翻译：

IsoLG 加合蛋白的免疫蛋白酶体加工对于高血压至关重要

背景：高血压的特点是CD8 + T细胞活化并浸润到外周组织。 CD8 + T 细胞的激活需要抗原蛋白的蛋白酶体加工。现已明确，isoLG（异左旋糖苷）诱导肽在高血压中具有抗原性；然而，IsoLG 会抑制组成型蛋白酶体。我们假设 isoLG 加合物的免疫蛋白酶体加工对于 CD8 + T 细胞激活和高血压炎症至关重要。方法：在鼠树突状细胞 (DC)、内皮细胞 (EC) 和 B8 成纤维细胞中研究 IsoLG 加合物加工。在用硼替佐米或免疫蛋白酶体抑制剂 PR957 治疗的C57BL/6小鼠中，并通过研究缺乏 3 个关键免疫蛋白酶体亚基的小鼠（三重敲除小鼠），研究了蛋白酶体和免疫蛋白酶体在 Ang II（血管紧张素 II）诱导的高血压中的作用。我们还检查了缺乏关键免疫蛋白酶体亚基 LMP7 的小鼠的高血压情况，特别是在 DC 或 EC 中。结果：我们发现氧化应激增加了 MHC-I（I 类主要组织相容性复合物）内 isoLG 加合物的存在，而免疫蛋白酶体过度表达则增强了这种情况。免疫蛋白酶体的药理学或遗传抑制可减轻高血压和组织炎症。 DC 或 EC 中 LMP7 的条件性缺失可减轻高血压和血管炎症。最后，我们定义了干扰素基因的先天免疫受体刺激剂和 TLR7/8（Toll 样受体 7/8）作为 EC 中 LMP7 表达驱动因素的作用。结论：这些研究定义了免疫蛋白酶体在 DC 中以前未知的作用和 ECs 在 CD8 + T 细胞激活中的作用。 DC 和 EC 中的免疫蛋白酶体对于将 isoLG 加合物呈递给 CD8 + T 细胞至关重要，而在内皮中，它引导 T 细胞归巢和浸润到特定组织。

更新日期：2024-04-17