ES‐62 Protects Against Collagen‐Induced Arthritis by Resetting Interleukin‐22 Toward Resolution of Inflammation in the Joints

Abstract

ObjectiveThe 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.MethodsThe 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 in the presence or absence of ES‐62.ResultsNeutralization 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.ConclusionIL‐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.

From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis

“…Again, underlining the importance of the particular microenvironment, whilst IL-22 appears to play a pathogenic role in the early systemic phase of disease, consistent with findings that mice deficient for IL-22 are resistant to CIA induction, 59 it acts to resolve established inflammation in the joint. 56 Moreover, whilst ES-62 does not significantly modulate levels of IL-22-producing cells in the draining lymph nodes, it increases those pertaining in the joints of animals with established CIA. Indeed, the anti-arthritic effect of ES-62 in the CIA model is dependent on such expression of IL-22, since neutralizing anti-IL-22 antibodies blocked ES-62 protection.…”

The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ

“…We have previously shown that ES-62, a phosphorylcholine (PC)-containing immunomodulatory glycoprotein secreted by the filarial nematode Acanthocheilonema viteae , is protective in mouse models of allergic123 and autoimmune456 disease. Such protection is associated with homeostatic resetting of the IL-23/IL-17/IL-22 inflammatory axis, which appears to become dysregulated in these inflammatory disorders: a key effector driving development of this type of inflammation is the dendritic cell (DC), which ES-62 targets by subverting TLR4 signalling789 to suppress aberrant DC-priming of Th17 cells and IL-17-producing γδ T cells24.…”

Immuno-Modulatory Effect and Therapeutic Potential of Brugia malayi Cystatin in Experimentally Induced Arthritis

“…ES-62 protein derived from A. viteae has been shown to exhibit reduction in the severity of inflammation in collagen induced arthritis (CIA) [1]. The administration of Ascaris suum or the treatment of whole worm extract effectively prevented zymogen induced arthritis in rats with amelioration of clinical symptoms of arthritis and synovitis in a dose dependent manner [19].…”

“…Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint swelling, synovial inflammation and cartilage destruction [1]. Though the aetiology of the disease is not fully understood, dysregulation of IL-17 production and activation of both T and B cells as well as macrophages are supposed to be the cause behind disease progression [1].…”

“…Though the aetiology of the disease is not fully understood, dysregulation of IL-17 production and activation of both T and B cells as well as macrophages are supposed to be the cause behind disease progression [1]. Current therapy for RA is based on generalized suppression of immune response through disease modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs [1]. However, these drugs have been shown to cause serious side effects in gastrointestinal tract, kidneys and central nervous system [2].…”