Macrophages are sentinels of the innate immune system that maintain tissue homeostasis and contribute to inflammatory responses. Their broad scope of action depends on both functional heterogeneity and plasticity. Small noncoding RNAs called microRNAs (miRNAs) contribute to macrophage function as post-transcriptional inhibitors of target gene networks. Genetic and pharmacologic studies have uncovered genes regulated by miRNAs that control macrophage cellular programming and macrophage-driven pathology. miRNAs control proinflammatory M1-like activation, immunoregulatory M2-like macrophage activation, and emerging macrophage functions in metabolic disease and innate immune memory. Understanding the gene networks regulated by individual miRNAs enhances our understanding of the spectrum of macrophage function at steady state and during responses to injury or pathogen invasion, with the potential to develop miRNA-based therapies. This review aims to consolidate past and current studies investigating the complexity of the miRNA interactome to provide the reader with a mechanistic view of how miRNAs shape macrophage behavior.

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