Effect of ADAR1 silencing in human monocyte-derived macrophages II

While its role in innate immunity is well established, the broader regulatory functions of ADAR1 in macrophages remain poorly defined. Here, we systematically profiled ADAR1 expression across human immune cells and identified a marked enrichment in macrophages, driven by selective usage of an alternative transcription start site during monocyte-to-macrophage differentiation.

ADAR1 binds, edits, and modulates key macrophage targets involved in efferocytosis, endocytosis, lysosomal processing, lipid metabolism, and proliferation in an isoform-specific manner. We further demonstrate that ADAR1 levels and activity are dynamically regulated in adipose tissue and liver during the progression of metabolic disease. Linked to this, macrophage specific ablation of ADAR1 co-cultured in organotypic 3D primary human spheroids and exposed to metabolic stress resulted in an exacerbated lipid accumulation phenotype.