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Inflammation, immunity, diet and sleep: who regulates who?

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, That’s the summary finding of a new Northwestern Medicine study in mice. The study used a new genetic switch technology to turn inflammation on and off in genetically modified mice. In inflammatory diseases, the body experiences an excess of a genetic factor known as NF-kappa beta (NF-kB), the study found. NF-kB is a transcription factor for the inflammatory 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. Senior author Dr. Joseph Bass, Professor of Medicine and director of the Center for Diabetes and Metabolism at Northwestern University Feinberg School of Medicine, explained: “NF-kB 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,”

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. 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. 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. 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.

Activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the genes Period, Cryptochrome and Rev-erb, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 from genome-wide to sites convergent with those bound by NF-κB. This was proven checking two cellular markers for gene expression, acetylated histone H3 and enrichment in RNA polymerase II. 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. How adult animals adapt to changes in nutrients and inflammation under normal and pathologic conditions may be influenced by the activation of NF-κB and its modulation of circadian function.

However, whether improper NF-κB activation may contribute to metabolic disease and aging in part through dysregulation of circadian systems remains an important question to be explored, particularly in regard to the determination of which neuronal cell types are influenced by NF-κB signaling in the brain. First author Dr. Hong explained: “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. Indeed, recent work has demonstrated essential roles for the circadian repressors Rev-Erb and E4BP4 in modulating the development and activity of adaptive Th17 lymphocytes and innate lymphoid cells, dendritic cells and macrophages, which mediate physiological responses to changes in the microbiota and extrinsic immune challenges“.

Seems therefore that the net between food intake, immune system, sleep and metabolism is more intertwined that thought earlier.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical. Biochemistry.

Scientific references

Hong HK et al. Genes Dev. 2018 Nov 1; 32(21-22):1367-79.

Gachon F et al. Genes Dev. 2018 Nov 1; 32(21-22):1359-60.

Maury E, Hong HK, Bass J. Diab. Metab. 2014;40(5):338-46.

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