Abstract
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 sequencing (RNA-seq) approach, we identified Mir146b as a microRNA whose expression progressively and unidirectionally declined with age in thioglycollate-elicited murine macrophages. Mir146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single-cell RNA-seq identified patterns of altered inflammation and interferon gamma signaling in Mir146b-deficient macrophages. Identification of Mir146b as a potential regulator of macrophage aging provides novel insights into immune dysfunction associated with aging.
Highlights
Macrophages are innate immune cells that perform critical surveillance functions and phagocytose pathogens and cellular debris (Mosser and Edwards, 2008; Wang et al, 2019)
In order to ensure that this preparation method provided a highly pure thioglycollate-elicited macrophage (TGEM) population for our studies and to determine if the age of the mouse from which the TGEMs were harvested impacted the degree of macrophage purity, we harvested peritoneal lavage exudates from five young (3 months old) and five old (20 months old) female C57Bl/6 mice 4 days post-thioglycollate induction
Continued on page the TGEM non-coding transcriptome by small RNA sequencing (RNA-seq) of female mice 3–30 months of age to probe for programmatic alterations in TGEM miRNA expression, which may contribute to the age-associated macrophage dysfunction that triggers the transition from physiologic aging to pathogenic inflammation and disease
Summary
Macrophages are innate immune cells that perform critical surveillance functions and phagocytose pathogens and cellular debris (Mosser and Edwards, 2008; Wang et al, 2019). Macrophages undergo broad programmatic changes with aging that manifest as abnormal macrophage activation and polarization and are phenotypically labeled as immunosenescence or inflammaging (Xia et al, 2016; Lin et al, 2018; Sene and Apte, 2014). This ageassociated shift in the macrophage phenotype from disease protective to disease promoting led us to hypothesize that alterations in the aged macrophage transcriptome may regulate this dysfunction. We demonstrate that expression of Mir146b progressively declines in the aging TGEM and is associated with significant mitochondrial dysfunction and abnormal macrophage activation and polarization, recapitulating the inflammaging phenotype
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