The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17–producing cellular network at multiple sites

Pineda, M.A., McGrath, M.A., Smith, P.C., Al-Riyami, L., Rzepecka, J., Gracie, J.A., Harnett, W. and Harnett, M.M. (2012) The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17–producing cellular network at multiple sites. Arthritis and Rheumatism, 64(10), pp. 3168-3178. (doi:10.1002/art.34581) (PMID:22729944)

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Abstract

Objective: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.

Methods: DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA.

Results: ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17–producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17–producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas.

Conclusion: Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Al-Riyami, Dr Lamyaa and Rzepecka, Dr Justyna and Gracie, Dr J Alastair and McGrath, Miss Mairi and Pineda, Dr Miguel
Authors: Pineda, M.A., McGrath, M.A., Smith, P.C., Al-Riyami, L., Rzepecka, J., Gracie, J.A., Harnett, W., and Harnett, M.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arthritis and Rheumatism
Publisher:John Wiley & Sons, Inc.
ISSN:0004-3591
ISSN (Online):2326-5205
Published Online:27 September 2012
Copyright Holders:Copyright © 2012 American College of Rheumatology
First Published:First published in Arthritis and Rheumatism 64(10):3168-3178
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOME)086852/Z/08/ZIII -IMMUNOLOGY