Signals of the Neuropilin-1-MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells.

Autor:	Rezaei M; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Martins Cavaco AC; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Seebach J; Institute of Anatomy and Vascular Biology, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Niland S; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Zimmermann J; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Hanschmann EM; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany; and., Hallmann R; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Schillers H; Institute of Physiology II, Westfalian Wilhelm University Münster, 48149 Münster, Germany., Eble JA; Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelm University Münster, 48149 Münster, Germany; johannes.eble@uni-muenster.de.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Mar 01; Vol. 202 (5), pp. 1559-1572. Date of Electronic Publication: 2019 Jan 28.
DOI:	10.4049/jimmunol.1801346
Abstrakt:	The neuropilin-1 (NRP1)-MET signaling axis regulates the motility of individual endothelial cells (ECs). It is unknown how this signaling pathway affects the endothelial barrier in coherent ECs forming a tight monolayer. We hypothesized that it is involved both in modulation of the endothelial barrier and in EC activation. To investigate the role of NRP1-MET signaling in inflammatory processes (e.g., systemic inflammatory response syndrome [SIRS] or snakebite-induced SIRS-like conditions), we employed the C-type lectin-related protein rhodocetin-αβ (RCαβ) as a specific trigger of this signal axis in ECs in vitro. In coherent HUVECs, RCαβ reinforced the actin cytoskeleton and increased cell stiffness, thus favoring vascular endothelial cadherin-mediated transmission of intercellular forces. Increased cell stiffness was associated with enhanced activation of RhoA and nuclear translocation of NF-κB. Simultaneously, RCαβ-triggered signaling via the NRP1-MET axis increased EC monolayer permeability, induced transcription of proinflammatory genes such as ICAM-1 and, consequently, leukocyte tethering. The RCαβ-induced transcriptome differed from that induced by hepatocyte growth factor, although in both cases the same tyrosine kinase, MET, was involved. This was due to RCαβ-mediated recruitment of the MET coreceptor NRP1 and additional Rho-mediated activation of the actomyosin system. RCαβ induced similar transcriptional and cellular changes if external shear forces were applied. These data highlight the modulatory role of NRP1 as MET coreceptor, and they explain how some snake venoms induce SIRS-like conditions. Additionally, this study demonstrates that inflammatory activation of coherent ECs is triggered by converging signals that are induced by NRP1-MET signaling and influenced by intercellular forces. (Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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