Abstract
ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of “pathogenic” hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 “rewiring” of SFs away from the hyper-responsive phenotype is associated with suppression of ERK activation, STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel “resolving” CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62’s mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62’s active PC-moieties mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.
Highlights
Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that targets articular joints, transforming the synovium into an inflamed, hyperplastic and invasive pannus that results in cartilage and bone destruction [1]
ES-62, an anti-inflammatory protein we discovered in the secretions of the filarial nematode Acanthocheilonema viteae, can prevent disease initiation and progression in mouse models of asthma, dermatitis, RA, SLE and the comorbidities arising from obesity-accelerated ageing
We show that its protection against arthritis is associated with an ability to stably reprogram stromal cells in the joint away from a pathogenic bone-damaging population to a novel “safe” phenotype
Summary
Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that targets articular joints, transforming the synovium into an inflamed, hyperplastic and invasive pannus that results in cartilage and bone destruction [1]. SFs adopt a mesenchymal/fibrotic phenotype [3], undergoing epigenetic rewiring in response to the hypoxia and inflammation generated in the microenvironment of the arthritic joint [4,5]. This rewiring is evidenced by changes in their global DNA methylation status, the hypomethylation of promoter regions associated with the de-repression of inflammatory genes driving SF transformation [1,4,6,7,8]. ES-62 acts to suppress the hyper-inflammatory phenotype of CIA-SFs [12] and prevent osteoclastogenesis [14]
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