Divergent Epigenetic and Transcriptomic Reprogramming of Monocyte Subpopulations in Systemic Lupus Erythematosus

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classical monocytes into intermediate monocytes and non-classical monocytes, assuming diverse roles. In this study, we investigated the epigenetic and transcriptomic profiles of these three monocyte subsets in an SLE cohort. In addition to common DNA methylation and transcriptomic alterations, we identified monocyte subset-specific alterations, especially in DNA methylation, which reflect an impact of SLE on the monocyte differentiation process. SLE classical monocytes exhibited a stronger proinflammatory profile, with an interferon signature and were primed for macrophage differentiation. SLE non-classical monocytes displayed a phenotype related to T cell differentiation regulation, and a Th17-promoting phenotype. Changes in monocyte proportions, DNA methylation and expression occurred in relation to disease activity and involved the STAT1 pathway. Integrating bulk datasets with single-cell RNA-seq data of SLE patients further supported the interferon signature in classical monocytes, associating intermediate and non-classical populations with exacerbated complement activation pathways. Our results indicate a subversion of the epigenome and transcriptome in monocyte differentiation toward non-classical subsets in SLE, impacting function, in relation to disease activity and progression.