PHILADELPHIA - An important link between the human body clock and the immune system has relevance for better understanding inflammatory and infectious diseases, discovered collaborators at the Perelman School of Medicine at the University of Pennsylvania and Trinity College, Dublin. In a study published this week in the Proceedings of the National Academy of Sciences, they report how a critical white blood cell called the macrophage, when exposed to bacteria, makes the biological clock inside the macrophage stop, allowing it to become inflamed.
The complex mechanism they have unraveled involves a microRNA called miR155, which destroys a key protein cog called BMAL-1 in the clock's mechanism. This protein allows the macrophage to make inflammatory proteins that effectively wake up the immune system.
"There may be times, such as during an acute bacterial infection, where it's advantageous for the immune system to use miR-155 to stop the macrophage clock and allow the body to clear the infection," said co-senior author Garret FitzGerald, MD, FRS, director of the Institute for Translational Medicine and Therapeutics and chair of the department of Systems Pharmacology and Translational Therapeutics at Penn. However, he added "when inflammation is present for long periods of time, as is the case for patients with a chronic disease like rheumatoid arthritis, this constant targeting of the clock may actually worsen disease." Guangrui Yang, MD, PhD, a research assistant professor of Systems Pharmacology and Translational Therapeutics at Penn is co-first author of the study.
"It's almost as if when we have an infection, the alarm in the macrophage clock goes off," explains co-first author Annie Curtis, PhD, senior research fellow Trinity College. "We have known for a long time that the immune system and body clock are interconnected, with our immune system responding differently to bacteria depending on the time of day."
This study illustrates the important role of the body clock in the immune response and provides a new rationale for a broad array of therapies. For example, approaches that restore clock function in treating inflammatory disorders and, perhaps attacking cancers at certain times of the day, may benefit from understanding this complex system of control.
In mice and in humans, the immune response to infection tends to be greater in the beginning of the night versus the early morning. The researchers found that this was dependent on the level of BMAL1, specifically in the macrophage. BMAL1 is an off switch for the immune system and is lower at night, allowing the immune system to be more active. Why this is the case is not fully clear, but a less-active immune system during the day (when the off-switch BMAL1 is higher) might mean that the human body doesn't over-react to infections (which are more likely to occur when we are active and coming into contact with sources of infection). However, if a large response is needed, then the macrophage can dampen BMAL1, and it does this via miR-155.
"We knew then that uncovering what causes the reduction in BMAL1 within the activated macrophage would be important to link the immune and clock system," explains co-senior author Luke O'Neill, PhD, also from Trinity College. The researchers also uncovered that miR-155 induction is greater in the evening than in the morning, providing one rationale as to why our immune response is more active at the transition into night. Therefore, this microRNA is a key link to how the immune system and biological clock control each other.
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This work was supported by grants from the National Heart. Lung, and Blood Institute (HL097800), the European Research Council, and the Science Foundation Ireland.
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Journal
Proceedings of the National Academy of Sciences