Assuntos
Neoplasias Encefálicas/etiologia , Síndrome do Jet Lag/complicações , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Ritmo Circadiano/efeitos da radiação , Humanos , Síndrome do Jet Lag/genética , Síndrome do Jet Lag/imunologia , Síndrome do Jet Lag/fisiopatologia , FotoperíodoRESUMO
Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
Assuntos
Senescência Celular/imunologia , Ritmo Circadiano/imunologia , Síndrome do Jet Lag/imunologia , Longevidade/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Senescência Celular/genética , Ritmo Circadiano/genética , Modelos Animais de Doenças , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Inflamação/imunologia , Inflamação/fisiopatologia , Síndrome do Jet Lag/fisiopatologia , Longevidade/genética , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Análise de Sequência de RNA , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. In this study, we show that experimentally induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified, leading to hypothermia and death after four consecutive weekly 6-h phase advances of the light/dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of proinflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However, polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus, and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related dysregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work.
