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Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.

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. Green open access

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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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