Chronic exposure to interleukin-10 drives inflammaging and accelerated tissue senescence

Abstract Interleukin (IL)-10, a major anti-inflammatory cytokine, can paradoxically have pro-inflammatory activities, which limits the efficacy of IL-10-based therapies. We previously showed that in vivo exposure to therapeutic doses of IL-10 reprograms T cells and promotes interferon (IFN)-γ-mediated emergency myelopoiesis. Here, we show that chronic IL-10 elevation in mice reprograms CD4+ and CD8+ T cells to display transcriptional and functional signatures of senescence. Furthermore, these T cells infiltrate and cause structural and functional alterations in the spleen, gonadal white adipose tissue and pancreas. Lack of T cells resulted in virtually no phenotype, whereas IFN-γ was only partly involved. Importantly, interrogation of several mouse and human datasets revealed a correlation between IL-10 levels and the IL-10-induced T cell signature with physiological aging. Altogether, we report a novel mouse model of sterile inflammaging and highlight a previously unappreciated role for IL-10 in accelerating aging, which is conserved in mice and humans. Our study opens new avenues on the basic biology and clinical use of IL-10.