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

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-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE164476 | GEO | 2021/08/24

REPOSITORIES: GEO

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Project description:To comprehensively characterize microRNAs (miRNA) expression and their target genes in thyroid cancer, we performed next-generation sequencing expression analysis of this disease. Recent studies have found that only the most abundant microRNAs mediate significant target suppression. We sequenced small RNA from 8 papillary thyroid carcinomas (PTC) with paired samples of normal thyroid tissue. We found that only a small set of abundant miRNAs are differentially expressed after pair-wise comparison (12 upregulated and 8 downregulated) reaching the minimum threshold amount to repress target mRNAs. We integrated computational prediction of potential targets and mRNA sequencing from the paired normal and tumor thyroid tissues from the same eight patients with PTC. The integrated analyses identified a master microRNA regulatory network in PTC that is involved in essential biological processes such as thyroid differentiation. As both mature products of miR-146b (miR-146b-5p and -3p) were among the most abundant upregulated in tumors, we unveil their target genes and found that miR-146b-3p specifically binds to the 3`UTR of PAX8 and NIS, leading to an impaired translation of the proteins and subsequently decreasing the iodide uptake of the cells. Furthermore, we show that mir-146b and PAX8 regulate each other, describing a novel regulatory circuit that determines the differentiated phenotype of PTC. In conclusion, our integrative genomic analysis uncovers the target genes of two of the most upregulated miRNAs and highlights the importance of a miR-146b3p-PAX8-NIS regulatory circuit that determines thyroid differentiation in thyroid cancer. Samples from Papillary Thyroid Carcinoma tumors (n=8) and contralateral normal thyroid tissue from the same patient (n=8) were collected at the Biobank of the Hospital Universitario La Paz (Madrid, Spain). The clinical characteristics of patients are summarized in Table S1. Surgically removed tissues were quickly frozen in liquid nitrogen until analysis. The samples were snap frozen on dry ice and stored at -80°C.

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

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