RESUMO
Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.
Assuntos
Relógios Circadianos/imunologia , Ritmo Circadiano/imunologia , Imunidade Adaptativa/genética , Animais , Cronoterapia , Relógios Circadianos/genética , Ritmo Circadiano/genética , Microbioma Gastrointestinal/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/genética , Imunoterapia , Linfócitos/imunologia , Modelos Imunológicos , Estações do AnoRESUMO
Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.
Assuntos
Ritmo Circadiano/imunologia , Sistema Imunitário/fisiologia , Imunidade Adaptativa/fisiologia , Animais , Contagem de Células Sanguíneas , Transtornos Cronobiológicos/imunologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/fisiologia , Suscetibilidade a Doenças , Cronofarmacoterapia , Retroalimentação Fisiológica/fisiologia , Regulação da Expressão Gênica/fisiologia , Hormônios/fisiologia , Humanos , Imunidade Humoral/fisiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Mamíferos/imunologia , Mamíferos/fisiologia , Camundongos , Modelos Imunológicos , Transcrição Gênica/fisiologiaRESUMO
Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.