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Endothelial Cell Secreted MIF Regulates Pericyte Contractility to Decrease Barrier Function
Author(s) -
Pellowe Amanda,
Hou Yue,
Harris Mariah,
Liu Rebecca,
Pober Jordan S,
Gonzalez Anjelica
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1210.6
Subject(s) - contractility , microbiology and biotechnology , focal adhesion , pericyte , tumor necrosis factor alpha , intercellular adhesion molecule 1 , endothelial stem cell , chemistry , downregulation and upregulation , macrophage migration inhibitory factor , cell adhesion molecule , cytokine , biology , signal transduction , immunology , endocrinology , in vitro , biochemistry , gene
Microvascular endothelial cells (EC) and pericytes (PC) regulate neutrophil (PMN) transmigration through a variety of mechanisms, including adhesion molecule expression and contractility. Specifically, the contraction of endothelial cells creates F‐actin docking structures rich in intercellular adhesion molecule 1 (ICAM‐1) expression and generates gaps between cells that allow for PMN transmigration. Recent evidence has alternatively suggested that PC relaxation, rather than contractility, results in the loss of focal adhesions, disassembly of stress fibers, and subsequent increase in PMN transmigration. Both in vivo and in vitro experimental systems of composite EC/PC microvascular constructs demonstrate that PC are less permissive to neutrophil transmigration in the absence of EC, suggesting that communication between EC and PC may regulate PC contractility. Here, we demonstrate that tumor necrosis factor alpha (TNFa) induced EC secretion of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF), which is accompanied by a TNFa induced upregulation of the MIF receptor (CD74) in PC, significantly decreases PC contractility. We confirm that TNFa mediated transmigration is differentially regulated by contractility. EC contractile ability is required to facilitate PMN transmigration through the formation of F‐actin docking sites and ICAM‐1 localization. In contrast, inhibition of PC contractility increases PMN transmigration via mechanisms that are not related to the loss of ICAM‐1 localization and F‐actin disassembly, but rather the loss of focal adhesion plaques, the loss of tension fibers and the formation of PC junctional gaps. We have confirmed that EC secreted MIF signaling results in the loss of PC focal adhesion plaques and significantly decreases PC contractility. This study suggests for the first time that EC paracrine signaling can mediate PC regulated PMN transmigration, and specifically that EC to PC MIF signaling may be an important factor for reducing PC barrier function during inflammation. Support or Funding Information Dubinsky Initiative