Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome

Abstract

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.

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

“…The effect of targeting this key integrator of inflammatory signalling is exemplified by the ability of ES-62 to suppress both the priming and maintenance of pathogenic Th17 and IL-17-producing γδ T cells in CIA by targeting MyD88 in both DCs and Th17 cells49. Moreover, this data explains at least in part how, despite signalling via TLR4/MyD88, ES-62 does not mimic canonical TLR4 ligands in driving proinflammatory responses and indeed can inhibit cellular responses to subsequent TLR-2, -4, -9, but not TLR-3, ligands4782232. However, ES-62 is not immunosuppressive per se allowing animals and humans, harbouring PC-containing molecules like ES-62 in their bloodstream, to mount protective responses against infection whilst dampening those resulting from aberrant inflammation (reviewed in refs 9 and 33).…”

Anti-Arthritic Activity of Schistosoma mansoni and Trichinella spiralis Derived-Antigens in Adjuvant Arthritis in Rats: Role of FOXP3+ Treg Cells

“…Multiple representative sections (3um thick) were cut and stained with hematoxylin and eosin (H&E) for microscopic examination [33]. The extent of joint inflammation and destruction of bone and cartilage was determined using a semi-quantitiative modified composite graded scale: grade 0, no signs of inflammation; grade 1, mild inflammation with hyperplasia of the synovial lining and minor cartilage damage; grades 2 through 4, increasing degrees of inflammatory cell infiltrate and destruction of bone and cartilage [34]. Immunohistochemical identification of forkhead box (foxP3) + T regulatory (Treg) cells in joint tissues was performed using rat anti-foxp3 antibody, clone 150D/E4 (eBioscience, Vienna, Austria).…”

Enteroparasitoses in Patients with Rheumatoid Arthritis

“…We also know that in addition to the risk of new infections, the possibility of reactivation of latent cases is also higher, which increases the chances of disease complications [4]. There has been a growing interest in researching the hypothesis that helminth may be involved in evolution of RA, although a great deal of further studies on this matter is necessary to evaluate the hypothesis in further detail [5]- [11]. The objective of the current study was to determine the prevalence of parasitic diseases in a population with RA, particularly focusing on the demographic of patients presenting with RA and parasitic infections.…”