T Cell-Expressed microRNA-155 Reduces Lifespan in a Mouse Model of Age-Related Chronic Inflammation

• Published in: The Journal of immunology (1950) 2020-04, Vol.204 (8), p.2064-2075
• Main Authors: Ekiz, H Atakan, Ramstead, Andrew G, Lee, Soh-Hyun, Nelson, Morgan C, Bauer, Kaylyn M, Wallace, Jared A, Hu, Ruozhen, Round, June L, Rutter, Jared, Drummond, Micah J, Rao, Dinesh S, O'Connell, Ryan M
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Disease Models, Animal; Female; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Longevity - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MicroRNAs - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1901484

Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a mice. Using single-cell RNA sequencing and flow cytometry, we found that miR-155 promotes the activation of effector T cell populations, including T follicular helper cells, and increases germinal center B cells and autoantibodies in mice aged over 15 months. Mechanistically, aerobic glycolysis genes are elevated in T cells during aging, and upon deletion of miR-146a, in a T cell miR-155-dependent manner. Finally, skewing T cell metabolism toward aerobic glycolysis by deleting mitochondrial pyruvate carrier recapitulates age-dependent T cell phenotypes observed in miR-146a mice, revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that T cell-specific miRNAs play pivotal roles in regulating lifespan through their influences on inflammaging.