CD8型
炎症
T细胞
蛋白酶体
细胞毒性T细胞
树突状细胞
免疫学
TLR7型
主要组织相容性复合体
免疫系统
抗原呈递
化学
细胞生物学
生物
先天免疫系统
Toll样受体
生物化学
体外
作者
Néstor de la Visitación,Wei Chen,Jaya Krishnan,Justin P Van Beusecum,V. Amarnath,Elizabeth M. Hennen,Shilin Zhao,Mohammad Saleem,Mingfang Ao,Sergey Dikalov,Anna Dikalova,David G. Harrison,David M. Patrick
标识
DOI:10.1161/circresaha.124.324068
摘要
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.
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