The circadian clock is an internal timekeeping system that regulates various physiological processes and behaviors in a 24-hour rhythm. It is present in almost all organisms, including humans, and influences numerous aspects of our biology, including sleep-wake cycles, hormone production, metabolism, and immune function. In recent years, emerging evidence has highlighted the intricate connection between the circadian clock and the immune system.

The core of the circadian clock is governed by a complex network of genes and proteins that form transcriptional-translational feedback loops. In mammals, the central pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives light cues from the environment through the retina. These cues help synchronize the internal clock with the external light-dark cycle, allowing the organism to adapt to the daily rhythmic changes (Mohawk, J. A., Green, C. B., & Takahashi, J. S., 2012).

The circadian clock controls the rhythmic expression of thousands of genes throughout the body, including those involved in immune regulation. Immune cells, such as lymphocytes, macrophages, and natural killer cells, exhibit time-of-day variations in their activity, cytokine production, and responsiveness to immune challenges (Silver, A. C., Arjona, A., Hughes, M. E., Nitabach, M. N., & Fikrig, E., 2012).

One way the circadian clock impacts the immune system is through the regulation of immune cell trafficking. Immune cells exhibit diurnal fluctuations in their migration patterns, with certain cells showing increased recruitment to specific tissues during particular times of the day. For example, in mice, lymphocyte trafficking to the skin is enhanced during the resting phase (nighttime), while migration to lymph nodes is more pronounced during the active phase (daytime) (Druzd, D., Matveeva, O., Ince, L., Harrison, U., He, W., Schmal, C., … & Gibbs, J. (2017).

Moreover, the circadian clock influences the innate and adaptive immune responses. It affects the activation and function of immune cells, including macrophages, dendritic cells, and T cells. Studies have shown that the response of these immune cells to pathogens and vaccines varies depending on the time of day. For instance, in mice, the ability of macrophages to clear bacteria is highest during the active phase, coinciding with elevated levels of pro-inflammatory cytokines (Silver, A. C., Arjona, A., Hughes, M. E., Nitabach, M. N., & Fikrig, E., 2012).

Furthermore, the circadian clock regulates the production of cytokines, which are essential signaling molecules involved in immune responses. Pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), exhibit diurnal variations in their production, with peaks occurring during the active phase. These fluctuations contribute to the time-dependent susceptibility to inflammatory diseases and influence the severity of immune responses (Curtis, A. M., Bellet, M. M., Sassone-Corsi, P., & O’Neill, L. A. (2014).

The circadian clock also influences the regulation of immune cell metabolism. Immune cells undergo metabolic changes during their activation and effector functions. The circadian clock controls the expression of metabolic genes in immune cells, thereby affecting their energy utilization, nutrient sensing, and mitochondrial activity. For example, disruptions in the circadian clock can lead to altered macrophage metabolism and impaired immune responses (Nguyen, K. D., Fentress, S. J., Qiu, Y., Yun, K., Cox, J. S., & Chawla, A., 2013).

Furthermore, disruptions in the circadian clock, such as shift work, jet lag, or chronic circadian rhythm disorders, can have detrimental effects on immune function. Shift workers, for instance, often experience immune dysregulation, increased susceptibility to infections, and a higher risk of inflammatory disorders, likely due to disturbances in the circadian regulation of immune responses (Scheiermann, C., Gibbs, J., & Ince, L., 2018).

The circadian clock exerts a significant influence on the immune system, regulating immune cell activity, cytokine production, immune cell trafficking, and immune cell metabolism. These rhythmic processes have implications for the susceptibility to infections, inflammatory diseases, and overall immune function. Understanding the interplay between the circadian clock and the immune system can provide insights into optimizing therapeutic strategies and timing interventions for various immune-related conditions.

References:

Mohawk, J. A., Green, C. B., & Takahashi, J. S. (2012). Central and peripheral circadian clocks in mammals. Annual Review of Neuroscience, 35, 445-462.
Silver, A. C., Arjona, A., Hughes, M. E., Nitabach, M. N., & Fikrig, E. (2012). Circadian expression of clock genes in mouse macrophages, dendritic cells, and B cells. Brain, Behavior, and Immunity, 26(3), 407-413.
Druzd, D., Matveeva, O., Ince, L., Harrison, U., He, W., Schmal, C., … & Gibbs, J. (2017). Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity, 46(1), 120-132.
Curtis, A. M., Bellet, M. M., Sassone-Corsi, P., & O’Neill, L. A. (2014). Circadian clock proteins and immunity. Immunity, 40(2), 178-186.
Nguyen, K. D., Fentress, S. J., Qiu, Y., Yun, K., Cox, J. S., & Chawla, A. (2013). Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science, 341(6153), 1483-1488.
Scheiermann, C., Gibbs, J., Ince, L., & Loudon, A. (2018). Clocking in to immunity. Nature Reviews Immunology, 18(7), 423-437.

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