ES-62 protects against collagen-induced arthritis by resetting interleukin-22 towards resolution of inflammation in the joints

Pineda, Miguel A and Rodgers, David T and Al-Riyami, Lamyaa and Harnett, William and Harnett, Margaret (2014) ES-62 protects against collagen-induced arthritis by resetting interleukin-22 towards resolution of inflammation in the joints. Arthritis and Rheumatism, 66 (6). 1492–1503. ISSN 0004-3591

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    Objective. The parasitic worm–derived immunomodulator ES-62 protects against disease in the mouse collagen-induced arthritis (CIA) model of rheumatoid arthritis (RA) by suppressing pathogenic interleukin-17 (IL-17) responses. The Th17 associated cytokine IL-22 also appears to have a pathogenic role in autoimmune arthritis, particularly in promoting proinflammatory responses by synovial fibroblasts and osteoclastogenesis. The present study was undertaken to investigate whether the protection against joint damage afforded by ES-62 also reflects suppression of IL-22. Methods. The role(s) of IL-22 was assessed by investigating the effects of neutralizing anti–IL-22 antibodies and recombinant IL-22 (rIL-22) on proinflammatory cytokine production, synovial fibroblast responses,and joint damage in mice with CIA, with versus without exposure to ES-62. Results. Neutralization of IL-22 during the initiation phase abrogated CIA, while administration of rIL-22 enhanced synovial fibroblast responses and exacerbated joint pathology. In contrast, after disease onset anti–IL-22 did not suppress progression, whereas administration of rIL-22 promoted resolution of inflammation. Consistent with these late antiinflammatory effects, the protection afforded by ES-62 was associated with elevated levels of IL-22 in the serum and joints that reflected a desensitization of the synovial fibroblast responses. Moreover, neutralization of IL-22 during the late effector stage of disease prevented ES-62–mediated desensitization of synovial fibroblast responses and protection against CIA. Conclusion. IL-22 plays a dual role in CIA, being pathogenic during the initiation phase while acting to resolve inflammation and joint damage during established disease. Harnessing of the tissue repair properties of IL-22 by ES-62 highlights the potential for joint-targeted therapeutic modulation of synovial fibroblast responses and consequent protection against bone damage in RA.

    ORCID iDs

    Pineda, Miguel A, Rodgers, David T, Al-Riyami, Lamyaa, Harnett, William ORCID logoORCID: and Harnett, Margaret;