Adrenergic Nerves Govern Circadian Leukocyte Recruitment to Tissues

Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA.
Immunity (Impact Factor: 21.56). 08/2012; 37(2):290-301. DOI: 10.1016/j.immuni.2012.05.021
Source: PubMed


The multistep sequence leading to leukocyte migration is thought to be locally regulated at the inflammatory site. Here, we show that broad systemic programs involving long-range signals from the sympathetic nervous system (SNS) delivered by adrenergic nerves regulate rhythmic recruitment of leukocytes in tissues. Constitutive leukocyte adhesion and migration in murine bone marrow (BM) and skeletal-muscle microvasculature fluctuated with circadian peak values at night. Migratory oscillations, altered by experimental jet lag, were implemented by perivascular SNS fibers acting on β-adrenoreceptors expressed on nonhematopoietic cells and leading to tissue-specific, differential circadian oscillations in the expression of endothelial cell adhesion molecules and chemokines. We showed that these rhythms have physiological consequences through alteration of hematopoietic cell recruitment and overall survival in models of septic shock, sickle cell vaso-occlusion, and BM transplantation. These data provide unique insights in the leukocyte adhesion cascade and the potential for time-based therapeutics for transplantation and inflammatory diseases.

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    • "Such a protocol resulted in increased cytokine production and lethality to high doses of lipopolysaccharide (LPS), a component of gram-negative bacteria (Castanon-Cervantes et al., 2010). The rhythms of leukocyte recruitment to tissues under physiological and inflammatory conditions are also disrupted after experimental jet lag (Scheiermann et al., 2012). In mice, shifted light schedules modified circadian expression of clock genes and cytolytic factors in natural killer (NK) cells, as well as their cytotoxic activity , which is associated with cancer development (Logan et al., 2012). "
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    ABSTRACT: The suprachiasmatic nucleus (SCN) drives circadian rhythms in behavioral and physiological variables, including the inflammatory response. Shift work is known to disturb circadian rhythms and is associated with increased susceptibility to develop disease. In rodents, circadian disruption due to shifted light schedules (jet lag) induced increased innate immune responses. To gain more insight into the influence of circadian disruption on the immune response, we characterized the inflammatory response in a model of rodent shift work and demonstrated that circadian disruption affected the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. Since food consumption is a main disturbing element in the shift work schedule, we also evaluated the inflammatory response to LPS in a group of rats that had no access to food during their working hours. Our results demonstrated that the shift work schedule decreased basal TNF-α levels in the liver but not in the circulation. Despite this, we observed that shift work induced increased cytokine response after LPS stimulation in comparison to control rats. Also, Kupffer cells (liver macrophages) isolated from shift work rats produced more TNF-α in response to in vitro LPS stimulation, suggesting important effects of circadian desynchronization on the functionality of this cell type. Importantly, the effects of shift work on the inflammatory response to LPS were prevented when food was not available during the working schedule. Together, these results show that dissociating behavior and food intake from the synchronizing drive of the SCN severely disturbs the immune response. © 2015 The Author(s).
    Journal of Biological Rhythms 05/2015; 30(4). DOI:10.1177/0748730415586482 · 2.77 Impact Factor
    • "A number of studies also point toward a circadian regulation of the recruitment of macrophages and monocytes to tissues, for example, in situations of infection. Accordingly, the expression of adhesion molecules is controlled by the circadian clock (Sato et al., 2014; Scheiermann et al., 2012). This is also the case for chemokines. "
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    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. © 2015 The Author(s).
    Journal of Biological Rhythms 04/2015; 30(4). DOI:10.1177/0748730415577723 · 2.77 Impact Factor
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    • "Scheiermann et al. have recently reported that the central SCN clock drives circadian rhythms in the expression of adhesion molecules (e.g., ICAM-1 and VCAM-1) on endothelial cells or chemokines/chemokine receptors (e.g., CCL2 and CXCR4) in tissue or leukocytes, which contributes to a time of day-dependent recruitment of leukocytes into the tissues such as the bone marrow and muscle [9]. The circadian activity of sympathetic nervous system driven by the central SCN clock likely regulates the expression of adhesion molecules or chemokine/chemokine receptors in a temporal manner, thereby controlling leukocyte migration. "
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    ABSTRACT: Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to "circadian rhythms." Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system "circadian clock" plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines.
    Journal of Immunology Research 04/2014; 2014(2):614529. DOI:10.1155/2014/614529 · 2.93 Impact Factor
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