Inflammatory cytokines shape a changing DNA methylome in monocytes mirroring disease activity in rheumatoid arthritis

Abstract

ObjectiveRheumatoid arthritis (RA) is a chronic systemic autoimmune disease that mainly targets joints. Monocytes and macrophages are critical in RA pathogenesis and contribute to inflammatory lesions. These extremely plastic cells respond to extracellular signals which cause epigenomic changes that define their pathogenic phenotype. Here, we interrogated how DNA methylation alterations in RA monocytes are determined by extracellular signals.MethodsHigh-throughput DNA methylation analyses of patients with RA and controls and in vitro cytokine stimulation were used to investigate the underlying mechanisms behind DNA methylation alterations in RA as well as their relationship with clinical parameters, including RA disease activity.ResultsThe DNA methylomes of peripheral blood monocytes displayed significant changes and increased variability in patients with RA with respect to healthy controls. Changes in the monocyte methylome correlate with DAS28, in which high-activity patients are divergent from healthy controls in contrast to remission patients whose methylome is virtually identical to healthy controls. Indeed, the notion of a changing monocyte methylome is supported after comparing the profiles of same individuals at different stages of activity. We show how these changes are mediated by an increase in disease activity-associated cytokines, such as tumour necrosis factor alpha and interferons, as they recapitulate the DNA methylation changes observed in patients in vitro.ConclusionWe demonstrate a direct link between RA disease activity and the monocyte methylome through the action of inflammation-associated cytokines. Finally, we have obtained a DNA methylation-based mathematical formula that predicts inflammation-mediated disease activity for RA and other chronic immune-mediated inflammatory diseases.

Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

“…IFNα from the IFN type 1 family has been shown to induce DNA methylation changes in monocytes in vitro [103]. Taken together, these data imply that the epigenetic alterations of the IFN type I genes in several cell types are likely to be a consequence of an aberrantly active IFN-I pathway in SLE.…”

“…Methylation levels in those regions were largely reversible during patient evolution over time. These associations made it possible to generate a predictive mathematical model to estimate patient activities from DNA methylation values [103].…”

The DNA methylation Profile of Undifferentiated Arthritis Patients Anticipates their Subsequent Differentiation to Rheumatoid Arthritis

“…Those alterations, which occur in regions that are functionally associated with inflammatory pathways, are common to those previously observed in other inflammatory diseases. In particular, enriched functional categories of inflammation, immune cell activation and cytokine signalling are also found in RA [6,28,29], SLE [30,31], asthma [32] and IBD [33] in comparable studies, supporting the idea that UA shares epigenetic similarities with other inflammatory diseases and thus can be molecularly considered as such. Furthermore, the identification of vast DNA methylation differences at the TNF locus as well as alterations at several CpGs within the HLA class II region (both at the DMP and DVP level) reasserts UA as an arthritide, such as RA, with which shares clinical characteristics [7,34–36]…”

“…Epigenetic alterations are associated with both genetic and environmentally-driven determinants which can in turn characterize pathogenic phenotypes. Specifically, DNA methylation and histone modifications, that are altered in multiple pathological contexts, are proposed to be both a causal factor [5] and a consequence of disease [6], as well as an intermediary for genetic susceptibility [7]. In all cases, the exhaustive study of these alterations through high-throughput technologies allows a detailed description and identification of novel molecular pathways that undergo alterations in a pathogenic context.…”

Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment

“…Recently it has been demonstrated that changes in the monocyte methylome reflects disease activity in RA patients. Indeed, some CpG sites of STAT3, FPR2, and TNFAIP8 correlate with DAS28 in RA monocytes [168]. However, the authors did not find any significant correlation between patient treatments (either biologic drugs or csDMARDs) and DNA methylation in RA monocytes.…”