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Title: Leucine-rich α-2-glycoprotein 1 suppresses endothelial cell activation through ADAM10-mediated shedding of TNF-α receptor
Authors: Pang, Kuin Tian
Ghim, Mean
Liu, Chenghao
Tay, Hui Min
Fhu, Chee Wai
Chia, Rui Ning
Qiu, Beiying
Sarathchandra, Padmini
Chester, Adrian H.
Yacoub, Magdi H.
Wilkinson, Fiona L.
Weston, Ria
Warboys, Christina M.
Hou, Han Wei
Weinberg, Peter D.
Wang, Xiaomeng
Keywords: Science::Medicine
Issue Date: 2021
Source: Pang, K. T., Ghim, M., Liu, C., Tay, H. M., Fhu, C. W., Chia, R. N., Qiu, B., Sarathchandra, P., Chester, A. H., Yacoub, M. H., Wilkinson, F. L., Weston, R., Warboys, C. M., Hou, H. W., Weinberg, P. D. & Wang, X. (2021). Leucine-rich α-2-glycoprotein 1 suppresses endothelial cell activation through ADAM10-mediated shedding of TNF-α receptor. Frontiers In Cell And Developmental Biology, 9, 706143-.
Journal: Frontiers In Cell And Developmental Biology
Abstract: Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1 -/- mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1 -/- mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.
ISSN: 2296-634X
DOI: 10.3389/fcell.2021.706143
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Mechanical and Aerospace Engineering 
Rights: © 2021 Pang, Ghim, Liu, Tay, Fhu, Chia, Qiu, Sarathchandra, Chester, Yacoub, Wilkinson, Weston, Warboys, Hou, Weinberg and Wang. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
MAE Journal Articles

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