Summary: Using new technology to turn inflammation on and off in mice, researchers discover inflammation may contribute to sleep disorders.
Source: Northwestern University.
Inflammation, which is the root cause of autoimmune disorders including arthritis, Type 1 diabetes, irritable bowel syndrome and Crohn’s disease, has unexpected effects on body clock function and can lead to sleep and shiftwork-type disorders, a new Northwestern Medicine study in mice found.
The study was published in the journal Genes & Development.
The study used a new technology — a genetic switch — to turn inflammation on and off in genetically modified mouse models. When researchers deactivated inflammation, the mouse was unable to tell what time it was and was unable to keep an intact rest-activity cycle.
In addition to this new technology, the study was novel because, for the first time, scientists saw a link between what causes inflammation and what controls the body’s clock.
In inflammatory diseases, the body experiences an excess of a genetic factor known as NF-kappa beta (NFKB), the study found. NFKB is a catalyst for a set of chain reactions, or pathway, that leads to the pain and tissue destruction patients feel in inflammatory diseases. That same chain-reaction catalyst also controls the body’s clock.
“NFKB alters the core processor through which we tell time, and now we know that it is also critical in linking inflammation to rest-activity patterns,” said senior author Dr. Joseph Bass, the Charles F. Kettering Professor of Medicine and director of the Center for Diabetes and Metabolism at Northwestern University Feinberg School of Medicine.
When people have sore muscles and take an ibuprofen to reduce the inflammation, they are essentially trying to turn down the activation of inflammation, which is similar to what the authors did in this study, Bass said.
The findings also have implications for diet and provide a detailed roadmap to understanding the fundamental mechanisms by which inflammation — including the inflammation that occurs when someone chronically consumes a high-fat diet — and likely other instigators lead to circadian disorders.
The scientists sought to understand how a high-fat diet might affect the perception of time at the tissue level, which is what led to their study of inflammation, said first author Hee-Kyung Hong, research assistant professor of endocrinology at Feinberg.
One of the reasons Western diet contributes to diabetes, cardiovascular disease and even certain cancers is thought to be the inappropriate trigger of inflammation, so a unifying idea is that impaired time-keeping may be one of the links between diet and disease.
“We don’t know the reasons, but this interaction between the inflammation and clocks is not only relevant to understanding how inflammation affects the brain and sleep-wake cycle but also how immune or fat cells work,” Hong said.
Funding: This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK090625 and R01DK100814, National Institute on Aging (NIA) grant P01AG011412, and Chicago Biomedical Consortium S-007 to J.B.; NIDDK grant R01DK108987, National Institute of Child Health and Human Development (NICHD) grant R01 HD089552, and American Diabetes Association (ADA) grant 1-17-IBS-137 to G.D.B.; and the Association de Langue Francaise pour l’Etude du Diabete et des Maladies Metaboliques (ALFEDIAM) grant to E.M.
Source: Kristin Samuelson – Northwestern University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Requirement for NF-κB in maintenance of molecular and behavioral circadian rhythms in mice” by Hee-Kyung Hong, Eleonore Maury, Kathryn Moynihan Ramsey, Mark Perelis, Biliana Marcheva, Chiaki Omura, Yumiko Kobayashi, Denis C. Guttridge, Grant D. Barish and Joseph Bass in Genes & Development. Published October 26 2018.
Requirement for NF-κB in maintenance of molecular and behavioral circadian rhythms in mice
The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period, Cryptochrome, and Rev-erb genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.