title: Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.
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.
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Silvia
authors.identifier: 0000-0002-9107-6291
authors.initials: S
authors.lastname: Dragoni
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hudson
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Bridget-Ann
authors.initials: BA
authors.lastname: Kenny
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Thomas
authors.identifier: 0000-0002-8428-720X
authors.initials: T
authors.lastname: Burgoyne
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: McKenzie
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Yadvinder
authors.initials: Y
authors.lastname: Gill
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Blaber
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: Peter
authors.identifier: 0000-0001-8234-1818
authors.initials: P
authors.lastname: Adamson
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
authors.forename: John
authors.identifier: 0000-0003-4496-2984
authors.initials: J
authors.lastname: Greenwood
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom p.turowski@ucl.ac.uk.
authors.forename: Patric
authors.initials: P
authors.lastname: Turowski
mesh_terms: D000199:Actins / Q000378:metabolism; D001921:Brain / Q000098:blood supply; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology; D054407:Chemokine CCL4 / Q000235:genetics / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000098:blood supply; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System; D055806:Microvessels; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; C515429:CCL3 protein, human; C066507:CCL4 protein, human; C508606:CXCL8 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C573420:ICAM1 protein, human; D016209:Interleukin-8; C496061:PXN protein, human; D051419:Paxillin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases