Cytohesin-2/ARNO: a novel bridge between cell migration and immunoregulation in synovial fibroblasts

Wang, Y., Çil, Ç., Harnett, M. M. and Pineda, M. A. (2022) Cytohesin-2/ARNO: a novel bridge between cell migration and immunoregulation in synovial fibroblasts. Frontiers in Immunology, 12, 809896. (doi: 10.3389/fimmu.2021.809896) (PMID:35095899) (PMCID:PMC8790574)

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Abstract

The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6 that has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process has previously been unexplored but we hypothesized that the pro-inflammatory milieu of inflamed joints locally induces activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway which can be rapidly activated by IL-1β. Such signalling promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating their precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.

Item Type:Articles
Additional Information:The work was funded by a Career Development award to MP from Versus Arthritis (21221), a China Scholarship Council (CSC) PhD scholarship awarded to YW and a YLSY Turkish Ministry of National Education Study Abroad Programme awarded to CC.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Cil, Mr Caglar and Wang, Yilin and Pineda, Dr Miguel
Authors: Wang, Y., Çil, Ç., Harnett, M. M., and Pineda, M. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Frontiers in Immunology
Publisher:Frontiers Media
ISSN:1664-3224
ISSN (Online):1664-3224
Published Online:12 January 2022
Copyright Holders:Copyright © 2022 Wang, Çil, Harnett and Pineda
First Published:First published in Frontiers in Immunology 12: 809896
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172504Harnessing glycan-dependent pathways in synovial fibroblasts to control chronic joint inflammation?Miguel PinedaVersus Arthritis (ARTRESUK)21221III - Immunology