RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

Pro-inflammatory (M1) macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cellular cytosine-to-uracil (C>U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here, we find that APOBEC3A-mediated RNA editing can also be induced by influenza or Maraba virus infections of normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of deleterious C>U RNA editing occurred in THOC5, encoding a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A in M1 macrophages reduces pro-inflammatory IL6, IL23A and IL12B gene expression, CD80 and CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis and glycolytic capacity. Thus, APOBEC3A plays an important role in transcriptomic and functional polarization of M1 macrophages.