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. The group has 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.
The group made several surprising findings. They found that the macrophages, essential for inflammation, and tissue repair, lost their circadian clock in inflamed joints. They 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. The group has 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.
The group discovered that the circuits in the liver responsible for storing, or using fat, and other essential nutrients showed a change in circadian organisation. They 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, Professor Ray proposes 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.