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

Area of Science:

• Immunology
• Aging Research
• Molecular Biology

Background:

• Aging-related chronic inflammation (inflammaging) is a risk factor for numerous human disorders.
• Mice lacking microRNA-146a (miR-146a-/-) exhibit shortened lifespans due to chronic inflammation.
• The specific mechanisms linking microRNAs to age-related inflammation and lifespan remain incompletely understood.

Purpose of the Study:

• To investigate the role of microRNA-155 (miR-155) in T cells in the shortened lifespan of miR-146a-/- mice.
• To elucidate the molecular mechanisms by which miR-155 influences immune cell function and metabolism during aging.
• To determine the impact of T cell metabolic reprogramming on age-dependent immune phenotypes.

Main Methods:

• Utilized single-cell RNA sequencing and flow cytometry in aged mice (over 15 months).
• Analyzed T cell populations, B cell activation, autoantibody production, and gene expression.
• Investigated the role of aerobic glycolysis and the mitochondrial pyruvate carrier in T cell metabolism.

Main Results:

• miR-155 in T cells was found to contribute to the shortened lifespan of miR-146a-/- mice.
• miR-155 promoted effector T cell activation (including T follicular helper cells), increased germinal center B cells, and elevated autoantibodies.
• Aerobic glycolysis genes were upregulated in T cells during aging, dependent on T cell miR-155 following miR-146a deletion. Deleting the mitochondrial pyruvate carrier recapitulated age-dependent T cell phenotypes.

Conclusions:

• T cell-specific microRNAs, including miR-155, play critical roles in regulating lifespan.
• miR-155 influences inflammaging by modulating T cell activation, B cell responses, and autoantibody production.
• Metabolic reprogramming of T cells towards aerobic glycolysis is sufficient to induce age-dependent immune cell dysfunction.