Crosstalk between the circadian clock circuitry and the immune system

Abstract

Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e.g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e.g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption.

FIGURE 1.

Schematic view of the crosstalk between the circadian system and different aspects of the immune system. Immune cells such as macrophages, monocytes, mast cells, B cells, and CD4⁺ T cells harbor intrinsic cell clocks (small clock symbols) that base on interlocked autoregulatory feedback loops of clock genes and their transcripts (see enlarged insert). This molecular clock in turn regulates clock-controlled genes and transcription factors, leading to rhythmic variations of cellular functions. Cellular immune rhythms are synchronized by the mammalian master clock (large clock symbol) that is located in the suprachiasmatic nuclei (SCN) in the anterior hypothalamus via time-dependent changes in the activity of the sympathetic nervous system (SNS), in the release of hormones (growth hormone [GH], prolactin, melatonin, cortisol) and in behavior that is linked to the sleep-wake cycle. As such the rest period (i.e., the dark period in humans and the light period in nocturnal rodents) is characterized by peak levels of proinflammatory hormones such as GH, prolactin (and melatonin in humans), and proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. In parallel, numbers of CD4⁺ T cells are highest, and on a functional level the responsivity to lipopolysaccharide (LPS) as well as Th1 and Th2 responses are likewise highest during sleep. During the active period, the hypothalamus pituitary adrenal (HPA) axis becomes activated and cortisol suppresses proinflammatory cytokine production, CD4⁺ T cell numbers, and allergic reactions. In contrast, natural killer (NK) cell numbers and functions peak during the active period and this rhythm is mainly regulated by the SNS and the release of epinephrine and norepinephrine. Disruption of this temporal organization of the immune system can lead to immunodeficiency (e.g., decreased tumor surveillance) and overshooting immune reactions (e.g., low-grade systemic inflammation). In addition to the circadian control of immune functions, immune mediators such as cytokines feed back to cellular clocks, the SCN, and sleep regulatory centers.