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Anti-GRP78 autoantibodies induce endothelial cell activation and accelerate the development of atherosclerotic lesions.
- Source :
-
JCI insight [JCI Insight] 2018 Dec 20; Vol. 3 (24). Date of Electronic Publication: 2018 Dec 20. - Publication Year :
- 2018
-
Abstract
- The 78-kDa glucose-regulated protein (GRP78) is an ER molecular chaperone that aids in protein folding and secretion. However, pathological conditions that cause ER stress can promote the relocalization of GRP78 to the cell surface (csGRP78), where it acts as a signaling receptor to promote cancer progression. csGRP78 also possesses antigenic properties, leading to the production of anti-GRP78 autoantibodies, which contribute to tumor growth. In contrast, the presence and role of anti-GRP78 autoantibodies in atherosclerosis is unknown. Here, we show that atherosclerotic-prone ApoE-/- mice develop circulating anti-GRP78 autoantibodies that bind to csGRP78 on lesion-resident endothelial cells. Moreover, GRP78-immunized ApoE-/- mice exhibit a marked increase in circulating anti-GRP78 autoantibody titers that correlated with accelerated lesion growth. Mechanistically, engagement of anti-GRP78 autoantibodies with csGRP78 on human endothelial cells activated NF-κB, thereby inducing the expression of ICAM-1 and VCAM-1, a process blocked by NF-κB inhibitors. Disrupting the autoantibody/csGRP78 complex with enoxaparin, a low-molecular-weight heparin, reduced the expression of adhesion molecules and attenuated lesion growth. In conclusion, anti-GRP78 autoantibodies play a crucial role in atherosclerosis development, and disruption of the interaction between anti-GRP78 autoantibodies and csGRP78 represents a therapeutic strategy.
- Subjects :
- Animals
Atherosclerosis pathology
Autoimmunity physiology
Cell Line, Tumor
Disease Models, Animal
Endoplasmic Reticulum Chaperone BiP
Female
Heat-Shock Proteins genetics
Humans
Intercellular Adhesion Molecule-1 metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
NF-kappa B metabolism
Proteostasis Deficiencies
RNA, Messenger metabolism
Signal Transduction
Vascular Cell Adhesion Molecule-1 metabolism
Atherosclerosis metabolism
Autoantibodies metabolism
Endothelial Cells metabolism
Heat-Shock Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 3
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 30568038
- Full Text :
- https://doi.org/10.1172/jci.insight.99363