Aging disrupts circadian gene regulation and function in macrophages

Autor: Eran Blacher, Connie Tsai, Lev Litichevskiy, Zohar Shipony, Chinyere Agbaegbu Iweka, Kai Markus Schneider, Bayarsaikhan Chuluun, H. Craig Heller, Vilas Menon, Christoph A. Thaiss, Katrin I. Andreasson
Rok vydání: 2021
Předmět:
Zdroj: Nat Immunol
Nature Immunology
ISSN: 1529-2916
1529-2908
Popis: Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation ofKlf4expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants ofKLF4revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmicKlf4expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.
Databáze: OpenAIRE
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