1. A reductionist, in vitro model of environmental circadian disruption demonstrates SCN-independent and tissue-specific dysregulation of inflammatory responses
- Author
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Adam C. Stowie, Ivory Ellis, Oscar Castanon-Cervantes, Kandis Adams, and Alec J. Davidson
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Male ,Physiology ,Circadian clock ,Pathology and Laboratory Medicine ,Toxicology ,Biochemistry ,Mechanical Treatment of Specimens ,Mice ,0302 clinical medicine ,Immune Physiology ,Medicine and Health Sciences ,Toxins ,Lung ,Cell Disruption ,Immune Response ,Chronobiology ,Multidisciplinary ,Suprachiasmatic nucleus ,Temperature ,Period Circadian Proteins ,Animal Models ,Circadian Rhythm ,Circadian Rhythms ,Circadian Oscillators ,Experimental Organism Systems ,Specimen Disruption ,Organ Specificity ,Cell disruption ,Medicine ,Female ,Suprachiasmatic Nucleus ,Cellular model ,Research Article ,Mice, 129 Strain ,Transgene ,Science ,Immunology ,Toxic Agents ,Bacterial Toxins ,Mice, Transgenic ,Mouse Models ,Biology ,Environment ,In Vitro Techniques ,Research and Analysis Methods ,Models, Biological ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,In vivo ,Diagnostic Medicine ,Circadian Clocks ,Animals ,Circadian rhythm ,Inflammation ,Interleukin-6 ,Biology and Life Sciences ,Endotoxins ,Mice, Inbred C57BL ,030104 developmental biology ,Specimen Preparation and Treatment ,Animal Studies ,Neuroscience ,030217 neurology & neurosurgery ,Spleen - Abstract
Environmental circadian disruption (ECD), characterized by repeated or long-term disruption in environmental timing cues which require the internal circadian clock to change its phase to resynchronize with the environment, is associated with numerous serious health issues in humans. While animal and isolated cell models exist to study the effects of destabilizing the relationship between the circadian system and the environment, neither approach provides an ideal solution. Here, we developed an in vitro model which incorporates both elements of a reductionist cellular model and disruption of the clock/environment relationship using temperature as an environmental cue, as occurs in vivo. Using this approach, we have demonstrated that some effects of in vivo ECD can be reproduced using only isolated peripheral oscillators. Specifically, we report exaggerated inflammatory responses to endotoxin following repeated environmental circadian disruption in explanted spleens. This effect requires a functional circadian clock but not the master brain clock, the suprachiasmatic nucleus (SCN). Further, we report that this is a result of cumulative, rather than acute, circadian disruption as has been previously observed in vivo. Finally, such effects appear to be tissue specific as it does not occur in lung, which is less sensitive to the temperature cycles employed to induce ECD. Taken together, the present study suggests that this model could be a valuable tool for dissecting the causes and effects of circadian disruption both in isolated components of physiological systems as well as the aggregated interactions of these systems that occur in vivo.
- Published
- 2019