Circadian Clocks in the Immune System

Abstract

The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…These immune cell clocks could act in two ways: by regulating the expression of molecules important for the synthesis and secretion of cytokines by these cells and by gating the response to the regulatory effects of cues from the central clock. A local direct regulation of immune cell functions (25,28) and a gating of the response to systemic cues (14,58,59) were shown to occur in rodents. However, we cannot exclude that the shift in the sleep-wake/feeding cycle might have contributed, to some extent, to the changes observed in the cytokine-release rhythm.…”

“…Among them, the innate and adaptive immune systems were shown to display daily rhythms in rodents and humans (14). This includes rhythms in cell counts in the blood (15)(16)(17)(18) and peripheral lymphoid organs (19), lymphocyte proliferation (20), cytokine levels in the blood (21)(22)(23)(24), and following ex vivo stimulation with various stimuli (16,19,(25)(26)(27)(28).…”

“…It is hypothesized that immune clocks are able to gate the integration of central clock's signals to limit or reinforce their effects at certain times of day (14).…”

Analysis of the circadian rhythm of biological processes in mouse liver and kidney

“…Нарушение нормальных циркадных ритмов может привести к развитию серьезных патологий, вклю чая рак, сердечно-сосудистые, нейродегенератив-ные, воспалительные заболевания и др. (Oishi et al, 2005;Cao et al, 2009;McCarthy, Welsh, 2012;Kettner et al, 2014;Fang et al, 2015;Labrecque, Cermakian, 2015;Sundar et al, 2015).…”

The tumor circadian clock: a new target for cancer therapy?

“…As a consequence of this, most cellular and physiological processes show 24 h oscillations. This is the case of many aspects of the immune system, including many immune cells and responses of relevance to cancer [3]. Also, major regulators of the cell cycle and tumor suppressor genes were shown to be regulated by the circadian clock, such as WEE1, c-MYC and p21 [4].…”