Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts

Corbet, M., Pineda, M. A. , Yang, K., Tarafdar, A., McGrath, S., NakagawaI, R., Lumb, F. E., Suckling, C. J., Harnett, W. and Harnett, M. M. (2021) Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts. PLoS Pathogens, 17(11), e1010069. (doi: 10.1371/journal.ppat.1010069) (PMID:34748611) (PMCID:PMC8601611)

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ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of “pathogenic” hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 “rewiring” of SFs away from the hyper-responsive phenotype is associated with suppression of ERK and STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel “resolving” CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62’s mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62’s active PC-moiety mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.

Item Type:Articles
Additional Information:The study was funded by awards from the Wellcome Trust (086852; and Versus Arthritis (21133; https://www. to M.M.H and W.H. M.A.P. is a Versus Arthritis Fellow (21221) and M.C. was awarded a Ph D studentship from the Wellcome Trust.
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and McGrath, Sarah and KUN, YANG and Lumb, Miss Felicity and Harnett, Professor William and Corbet, Marlene and Tarafdar, Ms Anuradha and Pineda, Dr Miguel
Authors: Corbet, M., Pineda, M. A., Yang, K., Tarafdar, A., McGrath, S., NakagawaI, R., Lumb, F. E., Suckling, C. J., Harnett, W., and Harnett, M. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN (Online):1553-7374
Published Online:08 November 2021
Copyright Holders:Copyright © 2021 Corbet et al.
First Published:First published in PLoS Pathogens 17(11): e1010069
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
162130ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOTR)086852/Z/08/ZIII - Immunology
172155MIMIC - Do parasitic worms and their secreted immunomodulators protect against musculosketal disease by impacting on the host microbiome?Margaret HarnettVersus Arthritis (ARTRESUK)21133III - Immunology
172504Harnessing glycan-dependent pathways in synovial fibroblasts to control chronic joint inflammation?Miguel PinedaVersus Arthritis (ARTRESUK)21221III - Immunology