METTL3 inhibition attenuates the macrophage type I interferon response

Abstract

Macrophages coordinate inflammatory responses to changing tissue conditions and invasion by pathogens. Post-transcriptional regulation of the transcriptome via RNA decay is a crucial element of these responses. N6-methyladenosine (m6A) deposition on mRNA constitutes one such post-transcriptional pathway, where the methyltransferase METTL3 and the oxygen dependent eraser ALKBH5 regulate m6A levels. We used TimeLapse-seq to measure transcriptome-wide abundance, decay, and transcription in THP1 macrophages comparing the effects of the METTL3 inhibitor STM2457 and hypoxia. We found no evidence that hypoxia and STM2457 affect RNA decay by a shared mechanism but discovered that METTL3 inhibition transcriptionally downregulates the interferon response through STAT1. Consequently, STM2457 treatment makes both THP1 and peripheral blood macrophages are more permissive to infection by the human coronavirus OC43. We conclude that macrophages depend on METTL3 activity to support the interferon response, an effect that appears distinct to macrophages and suggests METTL3 inhibitors could control macrophage driven inflammation.