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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Abstract
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; https://wellcome.org/) and Versus Arthritis (21133; https://www. versusarthritis.org/) 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. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Corbet, Marlene and Harnett, Professor Margaret and Tarafdar, Ms Anuradha and Lumb, Miss Felicity and Harnett, Professor William and McGrath, Sarah and Pineda, Dr Miguel and KUN, YANG |
| 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 > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | PLoS Pathogens |
| Publisher: | Public Library of Science |
| ISSN: | 1553-7366 |
| 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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