PMID- 35212196
OWN - NLM
STAT- MEDLINE
DCOM- 20220630
LR  - 20220718
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Linking)
VI  - 74
IP  - 7
DP  - 2022 Jul
TI  - Critical Role of Notch-1 in Mechanistic Target of Rapamycin Hyperactivity and 
      Vascular Inflammation in Patients With Takayasu Arteritis.
PG  - 1235-1244
LID - 10.1002/art.42103 [doi]
AB  - 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 gamma-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-1(high) , 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.
CI  - (c) 2022 American College of Rheumatology.
FAU - Jiang, Wanwan
AU  - Jiang W
AD  - Soochow University, Suzhou, China.
FAU - Sun, Mengyao
AU  - Sun M
AD  - First Hospital of Jilin University, Changchun, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - Soochow University, Suzhou, China.
FAU - Zheng, Ming
AU  - Zheng M
AD  - Soochow University, Suzhou, China.
FAU - Yuan, Zixin
AU  - Yuan Z
AD  - Soochow University, Suzhou, China.
FAU - Mai, Shixiong
AU  - Mai S
AD  - China-Japan Union Hospital of Jilin University, Changchun, China.
FAU - Zhang, Xin
AU  - Zhang X
AD  - China-Japan Union Hospital of Jilin University, Changchun, China.
FAU - Tang, Longhai
AU  - Tang L
AD  - Suzhou Blood Center, Suzhou, China.
FAU - Liu, Xiyu
AU  - Liu X
AD  - China-Japan Union Hospital of Jilin University, Changchun, China.
FAU - Wang, Chunhong
AU  - Wang C
AD  - Soochow University, Suzhou, China.
FAU - Wen, Zhenke
AU  - Wen Z
AUID- ORCID: 0000-0003-0542-0349
AD  - Soochow University, Suzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220602
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptor, Notch1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Inflammation
MH  - *Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice
MH  - RNA, Small Interfering
MH  - *Receptor, Notch1/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Takayasu Arteritis/metabolism
EDAT- 2022/02/26 06:00
MHDA- 2022/07/01 06:00
CRDT- 2022/02/25 05:44
PHST- 2022/02/03 00:00 [revised]
PHST- 2021/09/27 00:00 [received]
PHST- 2022/02/17 00:00 [accepted]
PHST- 2022/02/26 06:00 [pubmed]
PHST- 2022/07/01 06:00 [medline]
PHST- 2022/02/25 05:44 [entrez]
AID - 10.1002/art.42103 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2022 Jul;74(7):1235-1244. doi: 10.1002/art.42103. Epub 2022 
      Jun 2.