Divergent Epigenetic and Transcriptomic Remodelling during Monocyte Subset Differentiation in Systemic Lupus Erythematosus [methylation]

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by systemic inflammation that involves various immune cell types. Monocytes are central players in promoting and regulating inflammation. Different monocyte subsets exist and change their proportions during physiological immune responses and under pathological conditions, including SLE, supporting different roles in inflammatory responses. In this study, we obtained the epigenetic and transcriptomic profiles of the three monocyte subsets, classical, intermediate and non-classical monocytes in an SLE cohort. We found different common and subset-specific alterations. While SLE classical monocytes had a stronger proinflammatory profile with an important interferon influence priming them towards macrophage differentiation, non-classical monocytes had a phenotype related to T cell differentiation regulation, with several indications pointing towards a Th17 promoting behavior. Integration of these bulk datasets with single-cell RNA-seq data of an SLE cohort shed light on the heterogeneity of our monocytes, confirming the interferon signature profile of classical monocytes and pointing towards intermediate and non-classical populations associated with exacerbated complement activation pathways, among others. With this analysis, we confirm the differential role of monocyte subsets in the pathogenesis of SLE and give insight into their regulatory mechanisms. DNA methylation analysis of sorted classical monocyte, intermediate monocyte and non-classical monocyte subsets from 20 SLE patients at flare and follow-up visit, and 10 healthy donors