Loss of macrophage miR-146b with aging contributes to inflammation and mitochondrial dysfunction

Macrophages undergo programmatic changes with age leading to altered cytokine polarization and immune dysfunction, shifting these critical immune cells from protective sentinels to disease promoters. The molecular mechanisms underlying macrophage inflammaging are poorly understood. Using an unbiased RNA-seq approach, we identified miR-146b as the only microRNA whose expression progressively and unidirectionally declined with age in murine macrophages. miR-146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single-cell RNA sequencing identified patterns of altered inflammation and interferon gamma signaling in miR-146b deficient macrophages. Identification of miR-146b as a potential regulator of macrophage aging provides novel insights into immune dysfunction associated with aging. Overall design: Peritoneal macrophages were harvested from 3-, 6-, 12-, 18-, 24- and 30-month-old C57Bl/6 mice or Lyz2; miR-146b macrophage/monocyte conditional knockout and littermate control mice.