MicroRNAs: At the Interface of Metabolic Pathways and Inflammatory Responses by Macrophages

Abstract

Macrophages are key cells of the innate immune system with functional roles in both homeostatic maintenance of self-tissues and inflammatory responses to external stimuli, including infectious agents. Recent advances in metabolic research have revealed that macrophage functions rely upon coordinated metabolic programs to regulate gene expression, inflammation, and other important cellular processes. Polarized macrophages adjust their use of nutrients such as glucose and amino acids to meet their changing metabolic needs, and this in turn supports the functions of the activated macrophage. Metabolic and inflammatory processes have been widely studied, and a crucial role for their regulation at the post-transcriptional level by microRNAs (miRNAs) has been identified. miRNAs govern many facets of macrophage biology, including direct targeting of metabolic regulators and inflammatory pathways. This review will integrate emerging data that support an interplay between miRNAs and metabolism during macrophage inflammatory responses, highlighting critical miRNAs and miRNA families. Additionally, we will address the implications of these networks for human disease and discuss emerging areas of research in this field.

Keywords: immunometabolism; inflammation; macrophage; macrophage polarization; metabolism; microRNA.

Figure 1

Polarized macrophages have differential metabolic programming. Inflammatory macrophages characteristically increase glucose uptake to fuel aerobic glycolysis, producing increased lactate and ATP production. The pentose phosphate pathway feeds off of the increased flux of glycolytic intermediates, resulting in heightened nucleotide and amino acid synthesis. Classically activated macrophages have a disrupted TCA cycle in two locations: at isocitrate dehydrogenase (IDH) and at succinate dehydrogenase (SDH). As a result, citrate and succinate accumulate and drive such functions as fatty acid and NO synthesis, antimicrobial itaconate production, and HIF1α activity to promote further glycolysis and inflammatory cytokine production. Arginine is differentially metabolized in polarized murine macrophages, producing the antimicrobial molecule NO in inflammatory macrophages. Anti-inflammatory macrophages are not as metabolically active compared to classically activated macrophages, and they utilize glutamine, glucose, and fatty acids to fuel the TCA cycle and OXPHOS. In alternatively activated macrophages, glutamine uptake drives UDP-GlcNAc production, which is important for N-glycosylation of cell surface receptors, such as CD206 and CD301. In anti-inflammatory murine macrophages, arginine is metabolized to ornithine, which promotes tissue repair through production of prolines and polyamines. White arrows indicate metabolic intermediates driving M1 or M2 activities. α-KG, alpha-ketoglutarate; ARG1, arginase; HIF1α, hypoxia-inducible factor 1α; IDH, isocitrate dehydrogenase; IRG1, immune-responsive gene 1; NOS2, nitric oxide synthase; PPP, pentose phosphate pathway; ROS, reactive oxygen species; SDH, succinate dehydrogenase.

Figure 2

Selected miRNAs that regulate macrophage metabolic and inflammatory pathways. miRNAs are involved in regulating a number of important processes in macrophages. Certain miRNAs, highlighted here, target inflammatory or metabolic pathways to regulate macrophage activities. Red (left): miRNAs that promote inflammatory polarization. Blue (right): miRNAs that promote anti-inflammatory polarization. MiR-125a has noted roles in promoting both inflammatory and anti-inflammatory macrophages, as indicated. Let-7e is part of the miR-99b~Let-7e~miR-125a cluster and acts coordinately with miRNAs in its cluster to have the functions shown.

Figure 3

Looking forward: cross-talk between microRNAs and Metabolism. miRNAs control metabolic processes, but it is still largely unclear whether metabolic programs regulate miRNA transcription, biogenesis, or function. Metabolically-induced mechanisms of miRNA regulation could include modifications to miRNA machinery proteins such as DROSHA, DICER, or AGO2, with global impacts on miRNA biogenesis; histone modifications that lead to chromatin remodeling and alterations in miRNA availability; changes in transcription factor activity that lead to up-regulation or down-regulation of specific miRNAs; and other possible mechanisms that have yet to be identified.