Time-of-Day-Dependent Trafficking and Function of Leukocyte Subsets
Authors: Robert Pick, Wenyan He, Chien-Sin Chen, Christoph Scheiermann
Journal: Trends in Immunology (2019)

Leukocytes infiltrate tissues in a time-of-day-dependent manner, depending on subset- and tissue-specific rhythms in promigratory factors. Murine neutrophils rhythmically infiltrate many organs and thereby change the phenotype of the respective tissue. Adaptive immune responses, which take weeks to develop, are under circadian control in mice, and strongly depend on the time of day when an initial stimulus is given. Leukocytes can cell-autonomously regulate their circadian oscillations in the murine host by responding to reactive oxygen species and altering the binding of HIF-1α to the clock protein BMAL1, thus governing chemokine CXCR4 expression. Glucocorticoids transcriptionally regulate the expression of the IL-7 receptor in a circadian manner in mice, thus driving rhythmic CXCR4 expression and CD4+ and CD8+ T cell redistribution across the body. The number of leukocytes circulating in blood in mammals is under circadian control (i.e., ∼24 h). We summarize here latest findings on the mechanisms governing leukocyte migration from the blood into various organs, focusing on the distinct leukocyte subtype- and tissue-specific molecules involved. We highlight the oscillatory expression patterns of adhesion molecules, chemokines, and their receptors that are expressed on endothelial cells and leukocytes, and which are crucial regulators of rhythmic leukocyte recruitment. We also discuss the relevance of clock genes for leukocyte function and migration. Finally, we compare immune cell rhythms under steady-state conditions as well as during inflammation and disease, and we postulate how these findings provide potential new avenues for therapeutic intervention. The number of leukocytes circulating in blood in mammals is under circadian control (i.e., ∼24 h). We summarize here latest findings on the mechanisms governing leukocyte migration from the blood into various organs, focusing on the distinct leukocyte subtype- and tissue-specific molecules involved. We highlight the oscillatory expression patterns of adhesion molecules, chemokines, and their receptors that are expressed on endothelial cells and leukocytes, and which are crucial regulators of rhythmic leukocyte recruitment. We also discuss the relevance of clock genes for leukocyte function and migration. Finally, we compare immune cell rhythms under steady-state conditions as well as during inflammation and disease, and we postulate how these findings provide potential new avenues for therapeutic intervention. Organisms exposed to the recurring environmental change of the daily light–dark cycle have adapted to these changes with a finely tuned internal clock mechanism. This mechanism entrains (see Glossary) to environmental cues such as light to anticipate recurring rhythms in food availability as well as potential threats [1Helm B. et al.Two sides of a coin: ecological and chronobiological perspectives of timing in the wild.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2017; 37220160246Crossref PubMed Scopus (76) Google Scholar]. With respect to the mammalian immune system, the most obvious oscillation is found in the daily changing numbers of circulating leukocytes in the blood. Preserved across many species, including humans [2Born J. et al.Effects of sleep and circadian rhythm on human circulating immune cells.J. 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This circadian rhythm in blood cell counts becomes apparent owing to a phase delay between the egress into the blood of cells from hematopoietic organs such as the bone marrow (BM) and their subsequent immigration into peripheral organs. Egress primarily occurs at the onset of the behavioral rest phase, and increases the numbers of cells in blood [6Lucas D. et al.Mobilized hematopoietic stem cell yield depends on species-specific circadian timing.Cell Stem Cell. 2008; 3: 364-366Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 7Mendez-Ferrer S. et al.Haematopoietic stem cell release is regulated by circadian oscillations.Nature. 2008; 452: 442-447Crossref PubMed Scopus (945) Google Scholar], whereas immigration of cells into peripheral organs predominantly occurs at the onset of the behavioral active phase. This in turn leads to decreased blood cell numbers during the active phase relative to the rest phase [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 8Scheiermann C. et al.Adrenergic nerves govern circadian leukocyte recruitment to tissues.Immunity. 2012; 37: 290-301Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. In mammals, environmental lighting conditions are captured by the eye and then converted into daily oscillations in physiology by a region within the anterior hypothalamus that is situated immediately above the optic chiasm, and is thus called the suprachiasmatic nucleus (SCN). The SCN is the master clock of the organism. 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It consists of multiple interlocking loops of the transcription factors BMAL1 [brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1, encoded by ARNTL], CLOCK (circadian locomotor output cycles kaput), PER1/2/3 (period circadian protein homologs), REV-ERB nuclear receptors α/β (encoded by NR1D1/2) and CRY1/2 (cryptochromes 1/2) [19Scheiermann C. et al.Clocking in to immunity.Nat. Rev. Immunol. 2018; 18: 423-437Crossref PubMed Scopus (249) Google Scholar, 20Curtis A.M. et al.Circadian clock proteins and immunity.Immunity. 2014; 40: 178-186Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar]. Although most studies have used floxed BMAL1 mouse models (Arntlflox) to ablate the circadian clock machinery, it is important to note that BMAL1 (in mice) also regulates the paralog BMAL2, making it difficult to attribute observed effects specifically to BMAL1. Leukocytes also use oxygen radicals, which are produced in a cyclical manner, as an additional means of synchronization [21Zhao Y. et al.Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice.Blood. 2017; 130: 1995-2005Crossref PubMed Scopus (46) Google Scholar]. Mechanistically, this is dependent on the control of reactive oxygen species by mitogen-activated protein kinase (MAPK) in leukocytes, altering the binding of hypoxia-inducible factor 1α (HIF-1α) to BMAL1, and ultimately regulating the expression of the chemokine receptor CXCR4 on these cells [21Zhao Y. et al.Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice.Blood. 2017; 130: 1995-2005Crossref PubMed Scopus (46) Google Scholar]. This mechanism appears to be more fundamental than the transcription–translation feedback loop because these radicals can also entrain hematopoietic cells devoid of nuclei (i.e., red blood cells) [22O'Neill J.S. Reddy A.B. Circadian clocks in human red blood cells.Nature. 2011; 469: 498-503Crossref PubMed Scopus (591) Google Scholar]. The physiological relevance of the circadian clock in regulating the day-to-day redistribution of immature hematopoietic stem and progenitor cells (HSPCs) [7Mendez-Ferrer S. et al.Haematopoietic stem cell release is regulated by circadian oscillations.Nature. 2008; 452: 442-447Crossref PubMed Scopus (945) Google Scholar] and mature immune cells between BM, blood, and peripheral tissues was demonstrated in complete BMAL1-deficient mice (Arntl−/−) [8Scheiermann C. et al.Adrenergic nerves govern circadian leukocyte recruitment to tissues.Immunity. 2012; 37: 290-301Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. Deletion of this core clock gene resulted in the abolition of time-of-day changes in blood circulating HSPCs [7Mendez-Ferrer S. et al.Haematopoietic stem cell release is regulated by circadian oscillations.Nature. 2008; 452: 442-447Crossref PubMed Scopus (945) Google Scholar] and in leukocyte migration to peripheral organs [8Scheiermann C. et al.Adrenergic nerves govern circadian leukocyte recruitment to tissues.Immunity. 2012; 37: 290-301Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. A similar phenotype was observed after surgical sympathetic denervation of tissues or in the absence of β2- or β3-adrenoreceptors [8Scheiermann C. et al.Adrenergic nerves govern circadian leukocyte recruitment to tissues.Immunity. 2012; 37: 290-301Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. These scenarios resulted in diminished oscillations in leukocyte homing, highlighting the fundamental importance of the sympathetic nervous system and local adrenergic innervation for daily leukocyte recruitment [8Scheiermann C. et al.Adrenergic nerves govern circadian leukocyte recruitment to tissues.Immunity. 2012; 37: 290-301Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. However, whether the SNS is generally involved in the underlying rhythmic entrainment of peripheral tissues [23Buijs R.M. et al.Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway.Eur. J. Neurosci. 1999; 11: 1535-1544Crossref PubMed Scopus (394) Google Scholar, 24Terazono H. et al.Adrenergic regulation of clock gene expression in mouse liver.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 6795-6800Crossref PubMed Scopus (235) Google Scholar] is debated given that peripheral circadian clock rhythmicity is retained in mice deficient in dopamine β-hydroxylase (Dbh−/−), and thus in the absence of adrenergic signaling [25Reilly D.F. et al.Peripheral circadian clock rhythmicity is retained in the absence of adrenergic signaling.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 121-126Crossref PubMed Scopus (45) Google Scholar]. In addition, the GDNF family receptor α2 (GFRα2) functions in the development/survival of cholinergic neurons, and recent observations in GFRα2-deficient mice (Gfra2−/−) have further implicated the parasympathetic nervous system (PNS) in the rhythmic regulation of leukocyte migration, counterbalancing the SNS [26Garcia-Garcia A. et al.Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.Blood. 2019; 133: 224-236Crossref PubMed Scopus (54) Google Scholar]. On the one hand, light onset in the morning acutely activates sympathetic β3-adrenoreceptors to induce the mobilization of hematopoietic cells from the BM in mice [7Mendez-Ferrer S. et al.Haematopoietic stem cell release is regulated by circadian oscillations.Nature. 2008; 452: 442-447Crossref PubMed Scopus (945) Google Scholar], but, on the other hand, light can also induce sympathetic cholinergic nerves to reduce homing, thereby facilitating the release of cells into blood [26Garcia-Garcia A. et al.Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.Blood. 2019; 133: 224-236Crossref PubMed Scopus (54) Google Scholar]. By contrast, at night, central parasympathetic cholinergic signals can dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. Owing to increased plasma adrenaline concentrations and HPA axis activity, the higher activation of β2-adrenoreceptors at this time can mediate the homing of cells to tissues in mice [26Garcia-Garcia A. et al.Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.Blood. 2019; 133: 224-236Crossref PubMed Scopus (54) Google Scholar]. Thus, sympathetic and parasympathetic nerves can serve opposite but cooperative roles to orchestrate rhythmic leukocyte release and homing. A recent report delineated that light and darkness can induce daily peaks of norepinephrine, TNF-α, and the hormone melatonin, which are essential for synchronized mature blood cell production and the repopulation of the HSPC pool within the murine BM [27Golan K. et al.Daily onset of light and darkness differentially controls hematopoietic stem cell differentiation and maintenance.Cell Stem Cell. 2018; 23: 572-585Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar]. These findings have suggested that there is important interplay between processes mediated by light and darkness in conjunction with processes that rely on components of the circadian clock. Leukocytes are recruited to tissues via a series of consecutive steps, beginning with their capture and rolling along the endothelial wall, followed by the induction of firm adhesion, intraluminal crawling, and transmigration from the bloodstream through the endothelial barrier into the tissue [28Ley K. et al.Getting to the site of inflammation: the leukocyte adhesion cascade updated.Nat. Rev. Immunol. 2007; 7: 678-689Crossref PubMed Scopus (3088) Google Scholar] (Box 1). Leukocyte recruitment includes processes such as extravasation and margination (Figure 1, Key Figure). Endothelial cell-specific BMAL1 deletion in mice (Cdh5–creERT2:Arntlflox) results in abolished time-of-day differences in the expression of VCAM-1 and ICAM-1, and abrogates rhythmic homing to peripheral tissues [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. This emphasizes the significant impact of endothelial-specific Bmal1 expression for the rhythmic change in leukocyte homing capacity. However, whether this link is directly mediated via binding of circadian transcription factors to the promoter regions of these molecules, or whether it is indirect, is currently unknown. In this review we summarize the latest findings on the molecular mechanisms that govern leukocyte subset- and organ-specific rhythmic recruitment and function in homeostasis and during inflammation in this rapidly growing field. Furthermore, we delineate the role of rhythmic leukocyte trafficking in various inflammatory diseases, and discuss the potential for therapeutic intervention in this process.Box 1Leukocyte RecruitmentLeukocytes adhere to the endothelium when PSGL-1 (P-selectin glycoprotein ligand 1) binds to a family of glycoproteins termed selectins (L-/P-/E-selectin). Leukocytes then roll on the endothelium and are exposed to various promigratory factors such as the chemokine CXCL1 (chemokine CXC motif ligand 1) that trigger G protein-coupled chemokine receptor signaling (e.g., CXCR2, CXC motif chemokine receptor 2). This leads to the activation of integrins such as LFA-1 (lymphocyte function-associated antigen 1 or CD11a/CD18), Mac-1 (macrophage-1 antigen or CD11b/CD18) on myeloid cells, and VLA-4 (very late antigen 4 or CD49d/CD29), as well as to the subsequent interaction with endothelial adhesion molecules ICAM-1 and ICAM-2 (intercellular adhesion molecules 1/2), or VCAM-1 (vascular cell adhesion molecule 1). This is crucial for mediating firm leukocyte arrest and transmigration across blood vessels. Leukocytes adhere to the endothelium when PSGL-1 (P-selectin glycoprotein ligand 1) binds to a family of glycoproteins termed selectins (L-/P-/E-selectin). Leukocytes then roll on the endothelium and are exposed to various promigratory factors such as the chemokine CXCL1 (chemokine CXC motif ligand 1) that trigger G protein-coupled chemokine receptor signaling (e.g., CXCR2, CXC motif chemokine receptor 2). This leads to the activation of integrins such as LFA-1 (lymphocyte function-associated antigen 1 or CD11a/CD18), Mac-1 (macrophage-1 antigen or CD11b/CD18) on myeloid cells, and VLA-4 (very late antigen 4 or CD49d/CD29), as well as to the subsequent interaction with endothelial adhesion molecules ICAM-1 and ICAM-2 (intercellular adhesion molecules 1/2), or VCAM-1 (vascular cell adhesion molecule 1). This is crucial for mediating firm leukocyte arrest and transmigration across blood vessels. Some of the first effector cells in innate immunity are neutrophils, which in humans make up the predominant leukocyte subset in blood. Under steady-state conditions, human and murine neutrophil blood counts oscillate in a circadian manner [14Ella K. et al.Circadian regulation of human peripheral neutrophils.Brain Behav. Immun. 2016; 57: 209-221Crossref PubMed Scopus (71) Google Scholar, 29Casanova-Acebes M. et al.Rhythmic modulation of the hematopoietic niche through neutrophil clearance.Cell. 2013; 153: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar]. Human neutrophils exhibit diurnal fluctuations in CD11a, ICAM-1, L-selectin, and chemokine receptor CXCR4 expression [30Niehaus G.D. et al.Circadian variation in cell-adhesion molecule expression by normal human leukocytes.Can. J. Physiol. Pharmacol. 2002; 80: 935-940Crossref PubMed Scopus (31) Google Scholar]. In mice, rhythmic expression of PSGL-1, L-selectin, CD11a, CD29, and the chemokine receptors CXCR2 and CXCR4 has been observed [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] (Figures 1 and 2 ). Neutrophils predominantly migrate to BM, lung, liver, spleen, and skin at the onset of the active phase of the mouse, which occurs in the evening [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 31Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (150) Google Scholar]. However, elegant studies using parabiotic mice (with an experimentally conjoined blood circulation) have demonstrated that neutrophils can also migrate to other tissues in a rhythmic manner, an observation that was not previously associated with neutrophil infiltration under homeostatic conditions, such as in lymph nodes (LNs) and muscle tissue [31Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (150) Google Scholar]. This phenomenon is of functional relevance because it can alter the whole transcriptional profile of the affected tissue [31Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (150) Google Scholar], suggesting that even modest amounts of neutrophil infiltration can change organ phenotypes. Rhythmic neutrophil trafficking to tissues involves a different combination of molecules specific for their respective organs: in the murine spleen neutrophil homing requires CD49d and L-selectin, whereas VCAM-1 is involved in their recruitment to the liver [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Owing to their relatively short lifespan, murine neutrophils age in blood over the course of a single day, during which they upregulate the expression of the homing receptor CXCR4 in addition to other molecules such as CD11b and ICAM-1, while at the same time losing L-selectin expression via increased shedding from the cell surface [32Zhang D. et al.Neutrophil ageing is regulated by the microbiome.Nature. 2015; 525: 528-532Crossref PubMed Scopus (483) Google Scholar]. This marks neutrophils for clearance in the BM [29Casanova-Acebes M. et al.Rhythmic modulation of the hematopoietic niche through neutrophil clearance.Cell. 2013; 153: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar]. Functional blockade of CXCR4 with its specific antagonist AMD3100 results in abolished rhythmicity of neutrophil numbers in blood owing to a marked reduction in their recruitment to the BM compared to vehicle-treated controls. This has demonstrated the fundamental importance of the circadian expression of CXCR4 in the rhythmic trafficking behavior of neutrophils [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Although it is well established that neutrophils are key cell types in inflammation, these investigations into circadian migration have now identified new trafficking routes for neutrophils under homeostatic conditions; consequently, the known tissue tropism of neutrophils is expanded beyond the generally accepted inflammatory routes. Human total monocyte populations [33Cuesta M. et al.Simulated night shift disrupts circadian rhythms of immune functions in humans.J. Immunol. 2016; 196: 2466-2475Crossref PubMed Scopus (80) Google Scholar], as well as murine inflammatory (CD115+Ly6Chi) [16Nguyen K.D. et al.Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes.Science. 2013; 341: 1483-1488Crossref PubMed Scopus (416) Google Scholar] and non-inflammatory monocytes (CD115+Ly6Clo) [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], exhibit circadian oscillations in their numbers. Similarly to neutrophils, monocyte counts peak during the behavioral resting phase of mice and humans and reach a minimum during the active phase [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. In mice, rhythmic monocyte homing occurs predominantly to the liver, lung, and BM [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] (Figure 1). Similarly to neutrophils, circadian variations in CXCR4 expression also regulate the release of monocytes from BM and thus impact on the overall numbers of circulating monocytes [34Chong S.Z. et al.CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses.J. Exp. Med. 2016; 213: 2293-2314Crossref PubMed Scopus (72) Google Scholar], although also affecting their homing behavior into other peripheral organs such as murine liver [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. In parallel, inflammatory monocytes express the chemokine CCL2 in a similar rhythmic manner. In mice, BMAL1 deficiency disrupts this CCL2 oscillation, leading to impaired daily trafficking of monocytes relative to wild-type (WT) animals [16Nguyen K.D. et al.Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes.Science. 2013; 341: 1483-1488Crossref PubMed Scopus (416) Google Scholar]. In addition, loss of BMAL1 in myeloid cells of Lyz2–cre:Arntlflox mice results in a proinflammatory phenotype, with higher IL-6 cytokine production in the morning compared to controls; this phenotype is likely due to the role of BMAL1 in acting as an inflammatory brake in this cell type [35Gibbs J.E. et al.The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 582-587Crossref PubMed Scopus (432) Google Scholar]. The resulting proinflammatory phenotype is of pathological relevance given that a higher inflammatory tone predisposes Lyz2–cre:Arntlflox mice to low-grade chronic inflammation, in turn resulting in obesity [16Nguyen K.D. et al.Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes.Science. 2013; 341: 1483-1488Crossref PubMed Scopus (416) Google Scholar]. Thus, these data collectively demonstrate that oscillatory expression in chemokines and their receptors can govern the rhythmic mobilization and homing behavior of monocytes as well as their inflammatory phenotypes. In common with other leukocyte subsets, eosinophil numbers exhibit circadian oscillations in blood during homeostasis [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 36Acland J.D. Gould A.H. Normal variation in the count of circulating eosinophils in man.J. Physiol. 1956; 133: 456-466Crossref PubMed Scopus (17) Google Scholar, 37Halberg F. et al.Eosinophil rhythm in mice: range of occurrence; effects of illumination, feeding, and adrenalectomy.Am. J. Physiol. 1953; 174: 109-122Crossref PubMed Scopus (61) Google Scholar]. These cells were among the first leukocyte subsets to be described as oscillatory in humans [36Acland J.D. Gould A.H. Normal variation in the count of circulating eosinophils in man.J. Physiol. 1956; 133: 456-466Crossref PubMed Scopus (17) Google Scholar]. In mice, eosinophil oscillations in blood can be abolished by targeting CXCR4 or ICAM-1 [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], likely by disrupting their time-of-day-dependent recruitment to lung and liver [3He W. et al.Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues.Immunity. 2018; 49: 1175-1190Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] (Figure 1). The accumulation of eosinophils within tissues is furthermore dependent on the serum concentrations of IL-5 [38Dent L.A. et al.Eosinophilia in transgenic mice expressing interleuki