Hypoxia and inflammation induce synergistic transcriptome turnover in macrophages

Macrophages are effector immune cells that experience substantial changes to oxygenation when transiting through tissues, especially when entering tumors or infected wounds. How hypoxia alters gene expression and macrophage effector function at the post-transcriptional level remains poorly understood. Here we use TimeLapse-seq to measure how inflammatory activation modifies the hypoxic response in primary macrophages. Nucleoside recoding sequencing allows derivation of steady-state transcript levels, degradation rates, and transcriptional synthesis rates from the same dataset. We find that hypoxia produces distinct responses from resting and inflammatory macrophages. Hypoxia induces destabilization of mRNA transcripts, though inflammatory macrophages substantially increase mRNA degradation compared to resting macrophages. Increased RNA turnover results in upregulation of ribosomal protein genes and downregulation of extracellular matrix components in inflammatory macrophages. Hypoxia induces gene expression changes similar to tumorigenic macrophages in solid tumor biopsies, including increased ribosomal protein expression, implying that post-transcriptional control contributes to translation regulation in tumorigenic macrophages.