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Leucine-Rich ?-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-? Receptor

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


Kuin Tian Pang

Mean Ghim

Chenghao Liu

Hui Min Tay

Chee Wai Fhu

Rui Ning Chia

Beiying Qiu

Padmini Sarathchandra

Adrian H. Chester

Magdi H. Yacoub

Fiona L. Wilkinson

Ria Weston

Christina M. Warboys

Han Wei Hou

Peter D. Weinberg

Xiaomeng Wang


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.


Pang, K. T., Ghim, M., Liu, C., Tay, H. M., Fhu, C. W., Chia, R. N., …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,

Journal Article Type Article
Acceptance Date Jun 9, 2021
Online Publication Date Jul 5, 2021
Publication Date Jul 5, 2021
Deposit Date Jul 6, 2021
Publicly Available Date Jul 6, 2021
Journal Frontiers in Cell and Developmental Biology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 9
Public URL


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