Topological localization of monomeric C-reactive protein determines proinflammatory endothelial cell responses.
The activation of endothelial cells (ECs) by monomeric C-reactive protein (mCRP) has been implicated in contributing to atherogenesis. However, the potent proinflammatory actions of mCRP on ECs in vitro appear to be incompatible with the atheroprotective effects of mCRP in a mouse model. Because mCRP is primarily generated within inflamed tissues and is rapidly cleared from the circulation, we tested whether these discrepancies can be explained by topological differences in response to mCRP within blood vessels. In a Transwell culture model, the addition of mCRP to apical (luminal), but not basolateral (abluminal), surfaces of intact human coronary artery EC monolayers evoked a significant up-regulation of MCP-1, IL-8, and IL-6. Such polarized stimulation of mCRP was observed consistently regardless of EC type or experimental conditions (e.g. culture of ECs on filters or extracellular matrix-coated surfaces). Accordingly, we detected enriched lipid raft microdomains, the major surface sensors for mCRP on ECs, in apical membranes, leading to the preferential apical binding of mCRP and activation of ECs through the polarized induction of the phospholipase C, p38 MAPK, and NF-κB signaling pathways. Furthermore, LPS and IL-1β induction of EC activation also exhibited topological dependence, whereas TNF-α did not. Together, these results indicate that tissue-associated mCRP likely contributes little to EC activation. Hence, topological localization is an important, but often overlooked, factor that determines the contribution of mCRP and other proinflammatory mediators to chronic vascular inflammation.
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Hai-Yun
HY
Li
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Jing
J
Wang
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Yue-Xin
YX
Wu
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Lin
L
Zhang
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Zu-Pei
ZP
Liu
the Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, Montréal, Québec H1T 2M4, Canada.
János G
JG
Filep
the Roosevelt University College of Pharmacy, Schaumburg, Illinois 60173, and.
Lawrence A
LA
Potempa
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China, the Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, China wuy@lzu.edu.cn.
Yi
Y
Wu
From the Key Laboratory of Cell Activities and Stress Adaptations of Ministry of Education of China, School of Life Sciences, Lanzhou University, Lanzhou 730000, China, jsr@lzu.edu.cn.
Shang-Rong
SR
Ji
D001775:Blood Circulation; D002097:C-Reactive Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020935:MAP Kinase Signaling System; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D010738:Type C Phospholipases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases
Atherosclerosis; C-Reactive Protein; Endothelial Dysfunction; Inflammation; Innate Immunity; Pentraxins; Polarized Activation