Abstract
Pro-inflammatory (M1) macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated 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 cellular 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-1ß 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.
Footnotes
(1) Commercial source of IFN1 is included (p.19). (2) Minor addition to Discussion point (p.14).