Dragoni, S;
Hudson, N;
Kenny, B-A;
Burgoyne, T;
McKenzie, JA;
Gill, Y;
Blaber, R;
... Turowski, P; + view all
(2017)
Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.
J Immunol
, 198
(10)
pp. 4074-4085.
10.4049/jimmunol.1600823.
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Abstract
Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4(+) lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.
Type: | Article |
---|---|
Title: | Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions. |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.4049/jimmunol.1600823 |
Publisher version: | http://dx.doi.org/10.4049/jimmunol.1600823 |
Language: | English |
Additional information: | Copyright © 2017 The Authors. This article is distributed under the terms of the CC BY 4.0 Unported license. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
URI: | https://discovery.ucl.ac.uk/id/eprint/1549487 |
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