A-to-I RNA editing remodeling across CD11b/CD14/CD16-defined synovial monocyte-macrophage cell states

Abstract

Knee osteoarthritis (OA) is a disabling whole-joint disease involving synovial inflammation and myeloid-cell activation. A-to-I RNA editing can regulate endogenous dsRNA sensing and protein recoding, but its dynamics across synovial monocyte-macrophage cell states remain unclear. We analyzed 12 RNA-seq libraries from sorted CD11b + CD14 − CD16 − , CD11b + CD14 + CD16 − , and CD11b + CD14 + CD16 + cells (hereafter we omit CD11b + for simplicity) derived from knee OA synovial fluid of four donors. A-to-I editing signals were quantified and cell-state-associated editing patterns and ADAR / MDA5 expression were examined. We detected editing signals at 228,717 previously annotated candidate A-to-I editing sites, predominantly intronic sites. RNA editing profiles separated the three cell states, with CD14 + CD16 + cells showing the strongest divergence. Global editing levels and ADAR2 expression showed CD14 − CD16 − < CD14 + CD16 − < CD14 + CD16 + . Differential editing analyses revealed extensive editing enhancement in CD14 + CD16 + cells, exemplified by recoding events in CIRBP and COPA gene where the editing residues are deeply conserved across vertebrates. Intronic editing was negatively associated with immune-relevant MDA5 expression. A-to-I RNA editing is dynamically modulated across monocyte-macrophage states and may contribute to innate immune tuning. Our results also indicate that RNA editing status might be used as a potential indicator of monocyte-macrophage states.