Leukocyte Trafficking: Time to Take Time Seriously
2019; Cell Press; Volume: 50; Issue: 2 Linguagem: Inglês
10.1016/j.immuni.2019.01.013
ISSN1097-4180
AutoresNatalia Reglero-Real, Loïc Rolas, Sussan Nourshargh,
Tópico(s)Immune Response and Inflammation
ResumoLeukocyte trafficking is a key component of steady-state tissue homing and in mounting an inflammatory response. Two recent publications in Immunity by He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar report on the diurnal regulation of these responses and the associated pathophysiological implications. Leukocyte trafficking is a key component of steady-state tissue homing and in mounting an inflammatory response. Two recent publications in Immunity by He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar report on the diurnal regulation of these responses and the associated pathophysiological implications. Leukocyte migration is a crucial element of immunity in health and disease. Under homeostatic conditions, immune cells shuttle between the vascular system and tissues and provide immune surveillance. In response to pathogenic and sterile insults, leukocytes are recruited to inflamed tissues to eliminate the cause of injury and contribute to tissue repair (Nourshargh and Alon, 2014Nourshargh S. Alon R. Leukocyte migration into inflamed tissues.Immunity. 2014; 41: 694-707Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar). Leukocyte trafficking is exquisitely regulated by locally generated directional cues and factors that induce vital changes in microvessels to promote vascular attachment and diapedesis of leukocytes. These responses occur via a sequence of well-characterized events, as described by the leukocyte adhesion cascade and mediated by adhesive molecules expressed on the cell surface of leukocytes and vascular cells (Nourshargh and Alon, 2014Nourshargh S. Alon R. Leukocyte migration into inflamed tissues.Immunity. 2014; 41: 694-707Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar). Although this established paradigm is applicable to most peripheral tissues, recruitment mechanisms may substantially vary depending on the inflammatory stimuli and tissue microenvironment, including endothelial cell (EC) and mural cell (pericyte) heterogeneity of different vascular beds, as well as specific structural organization, rheological features, and local cellular composition of different organs. Furthermore, it is now well accepted that a wide variety of additional parameters, such as age, gender, diet, gut microbiota, metabolism, and genetics, can impact the profile and mechanisms of leukocyte trafficking (Franceschi et al., 2018Franceschi C. Garagnani P. Parini P. Giuliani C. Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases.Nat. Rev. Endocrinol. 2018; 14: 576-590Crossref PubMed Scopus (1013) Google Scholar). Recent studies have added circadian rhythm to this list, demonstrating the importance of diurnal rhythmicity as a regulator of leukocyte trafficking (Scheiermann et al., 2013Scheiermann C. Kunisaki Y. Frenette P.S. Circadian control of the immune system.Nat. Rev. Immunol. 2013; 13: 190-198Crossref PubMed Scopus (604) Google Scholar). Circadian rhythm refers to any biological process that displays oscillations during a period of ∼24 h. Such autonomous fluctuations can be aligned to overlap with the daily rotation of the Earth by the use of environmental cues such as light patterns (Scheiermann et al., 2013Scheiermann C. Kunisaki Y. Frenette P.S. Circadian control of the immune system.Nat. Rev. Immunol. 2013; 13: 190-198Crossref PubMed Scopus (604) Google Scholar). Amongst the many immune responses that show circadian rhythm, probably the most striking is the number of blood-circulating leukocytes, which peaks during the night for humans and during the day for rodents. In mice, this rhythmic behavior correlates with increased bone-marrow output at the beginning of the light phase and increased leukocyte exit from the circulation during the night (Casanova-Acebes et al., 2013Casanova-Acebes M. Pitaval C. Weiss L.A. Nombela-Arrieta C. Chèvre R. A-González N. Kunisaki Y. Zhang D. van Rooijen N. Silberstein L.E. et al.Rhythmic modulation of the hematopoietic niche through neutrophil clearance.Cell. 2013; 153: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, Scheiermann et al., 2013Scheiermann C. Kunisaki Y. Frenette P.S. Circadian control of the immune system.Nat. Rev. Immunol. 2013; 13: 190-198Crossref PubMed Scopus (604) Google Scholar). Through conducting an organism-wide assessment of pro-migratory molecules, He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar identified distinct molecular migratory codes responsible for recruitment of different leukocyte subsets to different organs over the course of the day. A key finding of this study is that rhythmic steady-state leukocyte trafficking into tissues (optimal during the dark phase) was regulated by a molecular clock in both leukocytes and ECs (Figure 1). Specifically, lineage-targeted genetic deletion of Bmal1 (brain and muscle Arnt-like protein-1), a transcription factor central to circadian clock function, in different leukocyte subsets or ECs ablated rhythmic leukocyte recruitment. This effect was linked to the temporal expression of pro-migratory molecules by leukocytes (e.g., integrins and chemokine receptors) and vascular beds (e.g., EC adhesion molecules ICAM-1 and VCAM-1). The functional implications of these findings were elegantly demonstrated through chronopharmacological studies in which optimal efficacy of pro-migratory blockers was time dependent. Collectively, these studies shed light on the molecular basis of time-of-day-dependent immune-cell trafficking in different organs. Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar further explored the rhythmicity of leukocyte recruitment, focusing on neutrophils. Neutrophils are the most abundant leukocytes in human blood, with a relatively short lifespan (∼12 h) in the circulation, though this issue is under exploration in different contexts (Hellebrekers et al., 2018Hellebrekers P. Vrisekoop N. Koenderman L. Neutrophil phenotypes in health and disease.Eur. J. Clin. Invest. 2018; 48: e12943Crossref PubMed Scopus (66) Google Scholar). Previous studies have shown that post mobilization from the bone marrow and during their circulation time in blood, neutrophils exhibit a natural phenotypic change that follows a diurnal regime and ultimately promotes rhythmic clearance of "aged neutrophils" from the circulation through relocation into tissues (e.g., bone marrow) (Casanova-Acebes et al., 2013Casanova-Acebes M. Pitaval C. Weiss L.A. Nombela-Arrieta C. Chèvre R. A-González N. Kunisaki Y. Zhang D. van Rooijen N. Silberstein L.E. et al.Rhythmic modulation of the hematopoietic niche through neutrophil clearance.Cell. 2013; 153: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Here, the term "aged neutrophils" refers to a population of CD62Llow CXCR4high mature neutrophils that are at the end of their blood circulation time (Casanova-Acebes et al., 2013Casanova-Acebes M. Pitaval C. Weiss L.A. Nombela-Arrieta C. Chèvre R. A-González N. Kunisaki Y. Zhang D. van Rooijen N. Silberstein L.E. et al.Rhythmic modulation of the hematopoietic niche through neutrophil clearance.Cell. 2013; 153: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, Zhang et al., 2015Zhang D. Chen G. Manwani D. Mortha A. Xu C. Faith J.J. Burk R.D. Kunisaki Y. Jang J.E. Scheiermann C. et al.Neutrophil ageing is regulated by the microbiome.Nature. 2015; 525: 528-532Crossref PubMed Scopus (470) Google Scholar). This population of neutrophils (∼40% of total blood neutrophils) peaks during daylight in mice, whereas non-aged or "fresh" neutrophils (CD62Lhigh) are most prevalent in the circulation at night. Most intriguingly, guided by gene expression analysis, acquisition of an aged neutrophil phenotype required a cell-autologous molecular program whereby BMAL1 regulated the expression of the chemokine CXCL2, a key CXCR2 ligand. In contrast to the pro-aging effects of CXCR2 activation, the chemokine receptor CXCR4 antagonized the attainment of neutrophil aging phenotype by blunting CXCR2 responses (Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Of note, in addition to neutrophils, the surface expression of CXCR4 was regulated in a rhythmic manner by numerous leukocyte subsets (He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Evidence for functional implications of this expression (He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) and the longer lifespan of most leukocyte subtypes (as compared to short-lived neutrophils) indicate a broader role for CXCR4 in rhythmic leukocyte trafficking beyond regulation of cell aging. Furthermore, because the ligand for CXCR4 (i.e., CXCL12) is not produced by neutrophils, neutrophil rhythmic homing is likely coordinated by extrinsic, potentially microenvironment-derived circadian signals, as indicated by He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar. In line with this, the unquestionable role of vascular mural and perivascular cells in leukocyte trafficking (Nourshargh and Alon, 2014Nourshargh S. Alon R. Leukocyte migration into inflamed tissues.Immunity. 2014; 41: 694-707Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar) begs the need for investigations into how functions of pericytes, mast cells, and tissue macrophages are controlled by time of day. Both studies show comparable results in terms of the impact of circadian rhythmicity on immune cell trafficking. Specifically, during homeostatic conditions, leukocytes emigrate from blood into tissues during dark phase, leading to a drop in blood leukocyte numbers (He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). With respect to aged neutrophils, through the use of genetically modified mouse models exhibiting constitutive or impaired neutrophil aging (i.e., via deletion of neutrophil Cxcr4 or Bmal1, respectively), Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar show aging to be essential for neutrophil clearance into tissues during the dark phase. Furthermore, leukocytes exhibited decreased homing to tissues during the light phase in a model of LPS-driven systemic inflammation (He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) and aged neutrophils (peaking during the light phase) showed impaired migration into inflamed tissues (Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). With respect to the latter, reduced neutrophil rolling, stemming from disrupted cortical actin architecture, was presented as a mechanism for defective inflammatory migration of aged neutrophils (Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Surprisingly, these cells spontaneously adhered to dermal vasculature under homeostatic conditions, suggesting expression of activated integrins on aged neutrophils, as previously described (Zhang et al., 2015Zhang D. Chen G. Manwani D. Mortha A. Xu C. Faith J.J. Burk R.D. Kunisaki Y. Jang J.E. Scheiermann C. et al.Neutrophil ageing is regulated by the microbiome.Nature. 2015; 525: 528-532Crossref PubMed Scopus (470) Google Scholar). In terms of breaching venular ECs, because the cell-autologous CXCL2-CXCR2 axis drives neutrophil TEM (transendothelial cell migration) (Girbl et al., 2018Girbl T. Lenn T. Perez L. Rolas L. Barkaway A. Thiriot A. Del Fresno C. Lynam E. Hub E. Thelen M. et al.Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis.Immunity. 2018; 49: 1062-1076.e6Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), the pro-migratory activity of neutrophil-derived CXCL2 could be particularly relevant in promoting tissue infiltration of aged neutrophils. So why does aging instruct a diurnal switch in the migratory profile of neutrophils? Remarkably, evidence is provided for the ability of aged neutrophils to exhibit enhanced antimicrobial capability in a model of Candida albicans infection by improving fungal clearance in kidneys (Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). At the same time, clearance of aged neutrophils from the circulation reduced the occurrence of intravascular thrombi post ischemia-reperfusion injury and protected mice in a model of acute myocardial infarction. Thus, it is proposed that tissue-infiltrated aged neutrophils provide a "ready-to-use" local immune protective mechanism while diminishing the risk of detrimental vascular inflammation. These findings raise several points. Fundamentally, as there is at present much interest in functional and phenotypic heterogeneity of neutrophils in health and disease (Hellebrekers et al., 2018Hellebrekers P. Vrisekoop N. Koenderman L. Neutrophil phenotypes in health and disease.Eur. J. Clin. Invest. 2018; 48: e12943Crossref PubMed Scopus (66) Google Scholar), it is unclear whether all neutrophils acquire an "aging" phenotype to a similar extent, within the same timeline, and via comparable mechanisms. Furthermore, the impact of factors such as chronic inflammation and physiological aging on "neutrophil aging," most notably in humans, and their properties require further explorations. Of note, although aged neutrophils were protective against Candida albicans infection where the kidney is a primary site for dissemination of the systemic fungus, decreased survival was observed in a model of sepsis when conducted during dark phase, i.e., time of maximal tissue infiltration of aged neutrophils. Thus, it is potentially possible that although aged neutrophils provide protection against local infections, neutropenia during the dark phase may render the host susceptible to systemic infections. However, as homeostatic clearance of blood neutrophils involved intravascular retention of cells in certain organs (e.g., in lungs) (He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), the relative contribution of such cellular compartmentalization to neutrophil-mediated intravascular immunity requires further exploration, as exemplified by elegant studies carried out in the lung microvasculature (Granton et al., 2018Granton E. Kim J.H. Podstawka J. Yipp B.G. The Lung Microvasculature Is a Functional Immune Niche.Trends Immunol. 2018; 39: 890-899Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Finally, contrary to the findings of Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, aged neutrophils have been reported to rapidly migrate into sites of inflammation and exhibit increased phagocytosis (Uhl et al., 2016Uhl B. Vadlau Y. Zuchtriegel G. Nekolla K. Sharaf K. Gaertner F. Massberg S. Krombach F. Reichel C.A. Aged neutrophils contribute to the first line of defense in the acute inflammatory response.Blood. 2016; 128: 2327-2337Crossref PubMed Scopus (126) Google Scholar), further indicating the need for greater understanding of the implications of diurnal immune cell trafficking. Collectively, these elegant studies strengthen the case for circadian control of immune cell functions. In particular, they provide insight into the physiological and pathological role of circadian variations in leukocyte trafficking, though there remain many unanswered questions, most notably in humans. Fundamentally, with greater understanding of this important concept, the findings of He et al., 2018He W. Holtkamp S. Hergenhan S.M. Kraus K. de Juan A. Weber J. Bradfield P. Grenier J.M.P. Pelletier J. Druzd D. et al.Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues.Immunity. 2018; 49: 1175-1190.e7Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and Adrover et al., 2019Adrover J.M. Del Fresno C. Crainiciuc G. Cuartero M.I. Casanova-Acebes M. Weiss L.A. Huerga-Encabo H. Silvestre-Roig C. Rossaint J. Cossío I. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50 (this issue): 390-402Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar endorse strategies aimed at exploiting time-based therapeutic interventions for optimal clinical benefit. Indeed, it is time to take time seriously in immunity and clinic practice! The authors are funded by the Wellcome Trust (098291/Z/12/Z to S.N.). Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to TissuesHe et al.ImmunityDecember 4, 2018In BriefLeukocytes continuously circulate throughout the body. He et al. demonstrate that trafficking patterns of major leukocyte subsets occur in a rhythmic manner dependent on the time-of-day-dependent expression of lineage- and tissue-specific factors. This influences the inflammatory response and leukemic tumor burden and translates to the migration behavior of human primary lymphocytes. Full-Text PDF Open AccessA Neutrophil Timer Coordinates Immune Defense and Vascular ProtectionAdrover et al.ImmunityJanuary 29, 2019In BriefNeutrophils display circadian oscillations in numbers and phenotype in the circulation. Adrover and colleagues now identify the molecular regulators of neutrophil aging and show that genetic disruption of this process has major consequences in immune cell trafficking, anti-microbial defense, and vascular health. Full-Text PDF Open Archive
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