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

Miguel Pineda, Mairi McGrath, Pauline Smith, Lamyaa Al-Riyami, Justyna Rzepecka, Alastair Gracie, William Harnett, Margaret Harnett

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Abstract

Among many survival strategies, parasitic worms secrete molecules to modulate host immune responses. One such product, ES-62, is protective in the collagen-induced arthritis (CIA) model of rheumatoid arthritis. As IL-17 has been reported to play a pathological role in the development of rheumatoid arthritis, we investigated whether targeting of IL-17 may explain the protection afforded by ES-62 in the CIA model. 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 cellular populations and in situ analysis of joint
inflammation. ES-62 was found to downregulate IL-17 responses in the CIA model. Firstly, it acts to inhibit priming and polarisation of IL-17 responses by targeting a complex IL-17-producing network, involving signalling between dendritic cells and γδ or CD4+ T cells. In addition, ES-62 directly targets Th17 cells by downregulating MyD88 expression to suppress responses mediated by IL-1 and TLR ligands. Moreover, ES-62 modulates migration of γδ T cells and this is reflected by direct suppression of CD44 upregulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there is strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. Such unique multi-site manipulation of the initiation and effector phases of the IL-17 inflammatory network could be exploited in the development of novel therapeutics for rheumatoid arthritis.
Original languageEnglish
Pages (from-to)3168–3178
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number10
Early online date27 Sep 2012
DOIs
Publication statusPublished - Oct 2012

Keywords

  • ES-62
  • collagen induced arthritis
  • inflammation
  • IL-17

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