RT Journal Article
SR Electronic
T1 ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.08.331942
DO 10.1101/2020.10.08.331942
A1 Marlene Corbet
A1 Miguel A Pineda
A1 Kun Yang
A1 Anuradha Tarafdar
A1 Sarah McGrath
A1 Rinako Nakagawa
A1 Felicity E Lumb
A1 William Harnett
A1 Margaret M Harnett
YR 2020
UL http://biorxiv.org/content/early/2020/10/08/2020.10.08.331942.abstract
AB The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an “aggressive” pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted “safe” phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct “protective” phenotype. Such unique behaviour signposts potential 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.Competing Interest StatementThe authors have declared no competing interest.