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- Title
Critical Role of Notch‐1 in Mechanistic Target of Rapamycin Hyperactivity and Vascular Inflammation in Patients With Takayasu Arteritis.
- Authors
Jiang, Wanwan; Sun, Mengyao; Wang, Ying; Zheng, Ming; Yuan, Zixin; Mai, Shixiong; Zhang, Xin; Tang, Longhai; Liu, Xiyu; Wang, Chunhong; Wen, Zhenke
- Abstract
Objective: Takayasu arteritis (TA) is a major type of large vessel vasculitis characterized by progressive inflammation in vascular layers. In our recent study we identified a central role of mechanistic target of rapamycin (mTOR) hyperactivity in proinflammatory T cell differentiation in TA. This study was undertaken to explore potential mechanisms underpinning T cell–intrinsic mTOR hyperactivity and vascular inflammation in TA, with a focus on Notch‐1. Methods: Notch‐1 expression and activity was determined according to Notch‐1, activated Notch‐1, and HES‐1 levels. We detected mTOR activity with intracellular expression of phosphorylated ribosomal protein S6. Differentiation of proinflammatory T cells was analyzed by detecting Th1 and Th17 lineage‐determining transcription factors. The function of Notch‐1 was evaluated using γ‐secretase inhibitor DAPT and gene knockdown using a short hairpin RNA (shRNA) strategy. We performed our translational study using humanized NSG mouse chimeras in which human vasculitis was induced using immune cells from TA patients. Results: CD4+ T cells from TA patients exerted Notch‐1high, leading to mTOR hyperactivity and spontaneous maldifferentiation of Th1 cells and Th17 cells. Blockade of Notch‐1 using DAPT and Notch‐1 shRNA efficiently abrogated mTOR complex 1 (mTORC1) activation and proinflammatory T cell differentiation. Mechanistically, Notch‐1 promoted mTOR expression, interacted with mTOR, and was associated with lysosomal localization of mTOR. Accordingly, systemic administration of DAPT and CD4+ T cell–specific gene knockdown of Notch‐1 could alleviate vascular inflammation in humanized TA chimeras. Conclusion: Expression of Notch‐1 is elevated in CD4+ T cells from TA patients, resulting in mTORC1 hyperactivity and proinflammatory T cell differentiation. Targeting Notch‐1 is a promising therapeutic strategy for the clinical management of TA.
- Subjects
RNA metabolism; CELL differentiation; FLOW cytometry; RAPAMYCIN; CELL receptors; MTOR inhibitors; TAKAYASU arteritis; GENE expression; VASCULAR diseases; INFLAMMATORY mediators; T cells; PHARMACODYNAMICS
- Publication
Arthritis & Rheumatology, 2022, Vol 74, Issue 7, p1235
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.42103