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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    • "Here are a few examples: 1. The recruitment of leukocytes to tissues (in situations of inflammation or under homeostasis) shows a circadian rhythm, which depends on the sympathetic nervous system (Scheiermann et al., 2012). However, the clock intrinsic to the leukocytes also plays a role, as illustrated by the rhythmic transcriptional regulation of the genes encoding chemokines involved in tissue recruitment (e.g., the rhythmic expression of the Ccl2 gene in monocytes and macrophages ) (Sato et al., 2014). "
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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; 2014:614529. DOI:10.1155/2014/614529 · 2.93 Impact Factor
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    • "high chemokine receptor CX3CR1 expression in these cells (Dimitrov et al. 2009). Accordingly, studies in mice showed a daily rhythm of leukocyte recruitment to bone marrow and skeletal muscle (Scheiermann et al. 2012). This rhythm is controlled by the central clock, via the sympathetic nervous system (SNS), which induces a daily oscillation of adhesion molecules and chemokines. "
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    ABSTRACT: The immune system is deeply interconnected with the endogenous 24-h oscillators of the circadian system. Indeed, the connection between these two physiological systems occurs at multiple levels and in both directions. On one hand, various aspects of the immune system show daily rhythms, which appear to be essential for healthy immune maintenance and proper immune response. On the other hand, immune responses cause changes in circadian rhythms, disrupting their delicate balance and manifesting in disease. Indeed, immune challenges cause various time-, gene-, and tissue-specific effects on circadian-regulated factors. This article reviews the possible mediators of the cross talk between the circadian clock and the immune system, in particular the inflammatory pathways. The rhythmic expression of cytokines and their receptors, as well as other rhythmically regulated humoral factors such as glucocorticoids, melatonin, leptin, or prostaglandins, could gate the effects of the immune response on the circadian system. In addition, systemic cues such as body temperature and neuronal connections between the brain and peripheral tissues may underlie the immune-circadian communication.
    Archivum Immunologiae et Therapiae Experimentalis 04/2014; 62(4). DOI:10.1007/s00005-014-0286-x · 3.18 Impact Factor
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