IEU Seminar: David Ray
OS6 Oakfield House or online via Zoom
Title: The relevance of circadian biology in medicine: how evolutionary ancient timing systems clash with modern life.
Abstract: Inflammation is essential for survival, and is responsible for organising the defence against infections, and recovery from injuries. A major cell type responsible for driving inflammation, and the recovery from injury is the macrophage. Inflammation, and the macrophages, are strongly regulated by the circadian clock. This is a conserved mechanism which allows anticipation of changes in the environment, eg from light to dark. The circadian clock, or body clock, is able to respond to changes in the environment eg light, and feeding time, and alters how cells, tissues, and whole animals respond to infection, or injury.
There remains a massive burden of chronic inflammatory disease, with associated metabolic co-morbidity. For example, rheumatoid arthritis (RA) is prevalent, and even with effective treatment is associated with accelerated cardiovascular disease. We have discovered that the circadian organisation of energy balance is disturbed by inflammation.
The circadian clock also plays a very important role in energy metabolism. The clock affects appetite, and feeding behaviour, as well as regulating how energy is stored in the body, how fat is stored during the day, and released for use as fuel overnight when fasting. Energy metabolism is also regulated by inflammation. The critical role for the circadian clock in both inflammation and energy metabolism, and the abnormal energy metabolism seen in chronic inflammation led us to test if the circadian organisation of energy metabolism was disrupted by inflammation.
We made several surprising findings. We found that the macrophages, essential for inflammation, and tissue repair, lost their circadian clock in inflamed joints. We have identified two major macrophage phenotypes affected by the core circadian machinery. In one BMAL1 action affects inflammatory cytokine response, in a REVERBa dependent manner. In the second the macrophage cytoskeleton, migratory, and phagocytic activity is high inhibited by BMAL1, in this case in a REVERBa independent and RhoA dependent manner. We have been investigating the BMAL1 mechanism of action, using primary macrophages harvested from animal at distinct circadian phases, with and without BMAL1. These studies have identified a network of genes that are circadian phase, and BMAL1 dependent.
We discovered that the circuits in the liver responsible for storing, or using fat, and other essential nutrients showed a change in circadian organisation. We discovered that fatty acids were being driven to form ceramides. These molecules were accumulating in liver, and muscle. Experimental manipulation of ceramides impacted the circadian amplitude in isolated liver cells.
In summary, the circadian machinery is responsible for regulating diverse elements of the inflammatory response. There are clear and direct actions through BMAL1 in the effector macrophages, and also we see actions on the systemic regulation of energy metabolism. Here, we propose that an adaptive response to acute inflammation becomes maladaptive, and may contribute to delayed resolution of inflammation, through the propagation of bioactive lipid species of the ceramide class.
Biography: Ray has made seminal discoveries in the circadian clock homeostatic control of inflammation and immunity, and has delivered the highest quality biomedical science that has advanced our understanding of the actions glucocorticoid hormones and drugs targeting the glucocorticoid receptor. His discovery of prevalent glucocorticoid resistance in human small cell lung cancer, which permits neuroendocrine gene expression, explained the ectopic ACTH syndrome, and he identified the genetic and epigenetic mechanisms that cause this resistance, with the latter linked to cigarette smoke carcinogens. These discoveries led to investigation of glucocorticoid action in inflammation. Here, Ray identified a pituitary neuroendocrine circuit linking inflammatory cytokines with activation of the hypothalamic-pituitary-adrenal axis. He elucidated how inflammation results in acquired changes in glucocorticoid sensitivity, and in the process identified a number of new glucocorticoid receptor regulatory proteins. His publication of the first in-silico model of the glucocorticoid receptor ligand binding domain, resulted in structure-based drug discovery, a Wellcome seeding drug discovery award, a patent, and foundation of a company. He also discovered surprising non-genomic mechanisms of glucocorticoid action, with implications for mitosis and cancer. Ray identified the importance of circadian rhythms for clinical medicine, and he has recently characterised the role of the circadian clock in macrophages, and in stromal cells, in affecting the inflammatory response to infection, and injury. His work revealed a critical role for the clock in determining anti-inflammatory drug responses, and demonstrated that these same processes are affected in human disease. Ray assembled, and led, the international consortium which identified new genes for sleep, and chronotype, and has shown that sleep is a primary driver of body composition, and neuropsychiatric traits. Finally, he has recently discovered how the circadian clock regulates the actions of glucocorticoids in the liver, thereby offering an explanation for aberrant glucocorticoid metabolism in human shift work.
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