Trends in Immunology
Volume 40, Issue 7, July 2019, Pages 584-597
Journal home page for Trends in Immunology

Feature Review
Special Issue: New Advances in Neutrophil Immunity
The Neutrophil Life Cycle

https://doi.org/10.1016/j.it.2019.04.013Get rights and content

Highlights

  • Neutrophils are produced by committed progenitors in the bone marrow and some extramedullary tissues.

  • The lifetime of mammalian neutrophils remains controversial.

  • Neutrophils are found in most healthy tissues at varying numbers.

  • Manipulation of the neutrophil life-cycle may be a promising strategy for the treatment of inflammatory diseases.

  • Differences among species may reflect the remarkable sensitivity of neutrophils to environmental conditions.

Neutrophils are recognized as an essential part of the innate immune response, but an active debate still exists regarding the life cycle of these cells. Neutrophils first differentiate in the bone marrow through progenitor intermediaries before entering the blood, in a process that gauges the extramedullary pool size. Once believed to be directly eliminated in the marrow, liver, and spleen, neutrophils, after circulating for less than 1 day, are now known to redistribute into multiple tissues with poorly understood kinetics. In this review, we provide an update on the dynamic distribution of neutrophils across tissues in health and disease, and emphasize differences between humans and model organisms. We further highlight issues to be addressed to exploit the unique features of neutrophils in the clinic.

Section snippets

The Neutrophil as a Double-Edged Sword in Health and Disease

Neutrophils (also named polymorphonuclear leukocytes) are phagocytes with an essential role in defending the host against invading pathogens, particularly bacteria and fungi 1., 2.. The killing of these organisms in phagosomes is mediated by: (i) fusion with lysosomes (granules) liberating cytotoxic proteins, peptides, and enzymes into the phagolysosome [3]; and (ii) activation of a membrane-bound NADPH-oxidase producing superoxide anions (O2) that in turn, are metabolized into hydrogen

The Mammalian Mitotic Neutrophil Pool

The neutrophil originates from myeloid lineage progenitor cells (common myeloid progenitors, CMPs) located within the bone marrow and extramedullary tissues, including the spleen. During the initial differentiation steps, the myeloid progenitors (myeloblasts) retain their propensity to differentiate into both the monocyte/macrophage lineage and the neutrophil lineage, as well as the other myeloid cells, namely, eosinophils and basophils. This common differentiation ends with the last

Intravascular Neutrophil Pools

Mature neutrophils are present in the vasculature in two pools: a free-flowing intravascular blood pool and a blood pool residing in certain tissues. This latter pool is generally referred to as the ‘marginated pool’. Early studies suggested that marginated neutrophils were in complete equilibrium with free-flowing cells and, therefore neutrophils from either pool were indistinguishable [52]. The major sites for marginated neutrophils in humans are the liver, spleen and bone marrow itself [53],

Neutrophil Dynamics in Blood and Tissues

Mouse and human neutrophils that are newly released into the bloodstream are endowed with distinct phenotypic properties in that they gradually change over time following circadian oscillations [76]. Moreover, at least in the mouse, these phenotypic changes parallel changes in their transcriptional and migratory properties of neutrophils 76., 77. (Figure 2, Key Figure). A major functional pathway affected by circadian rhythms is the rearrangement of the actin cytoskeleton over time, leading to

Concluding Remarks

The variety of kinetics and functions described for neutrophils is consistent with the emerging view that these cells are multifaceted. At least part of the neutrophil pool is essential in host defense against invading microorganisms and is crucial for a successful immune response. On the negative side, neutrophils are involved in the pathogenesis of a plethora of inflammatory diseases and can, in certain instances, suppress antitumor responses. Thus, it is clear that neutrophils may become

Clinician’s Corner

  • Neutrophils are among the principal effectors of the innate immune response and are instrumental in the first line of defense against invading microbes.

  • While there may be important differences between human neutrophils and those of other mammalian species, much has been learned from studies in transgenic animal models.

  • The production, circulation, and clearance of neutrophils is altered by inflammatory stimuli, such as those encountered in acute conditions, such as bacteremia, and chronic

Outstanding Questions

  • What are the real transit times of neutrophils in blood, bone marrow, and tissues? These times may provide insights into the non-immune roles and pathogenic potential of neutrophils in tissues.

  • What is the evolutionary basis for the diurnal behavior of neutrophils? Gating antimicrobial functions or protecting the tissues of the host are possible benefits of this behavior.

  • What are the mechanisms of neutrophil clearance in mice and humans? In which tissues does clearance occur? Understanding such

Acknowledgments

The work in the authors laboratories is funded by (ERC) Medical Research Council, Wellcome Trust, GlaxoSmithKline, MedImmune, the NIHR Cambridge Biomedical Research Centre, British Heart Foundation, National Institute for Health, Cambridge NIHR Biomedical Research Centre, the MCIU (Ministerio de Ciencia, Innovación y Universidades), the Pro-CNIC Foundation, the Dutch Science Agenda (NWA) and the Netherlands Organization for Scientific Research (NWO). The CNIC is a Severo Ochoa Center of

Glossary

Chédiak–Higashi syndrome
caused by deficiency in a gene required for lysosomal trafficking and phagocytosis that results in immune deficiency and albinism.
Chronic granulomatous disease (CGD)
immunodeficiency characterized by mutations in genes needed for the generation of ROS in granulocytes.
Common myeloid progenitors (CMPs)
type of hematopoietic progenitors that give rise to all myeloid-lineage cells in adult hematopoiesis.
Compensatory anti-inflammatory response syndrome (CARS)
comprises a period

References (129)

  • O. Marini

    Mature CD10+ and immature CD10 neutrophils present in G-CSF-treated donors display opposite effects on T cells

    Blood

    (2017)
  • P.H.C. Leliefeld

    Differential antibacterial control by neutrophil subsets

    Blood Adv.

    (2018)
  • S. Basu

    Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation

    Blood

    (2002)
  • N. Farahi

    Use of 111-Indium-labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects

    Blood

    (2012)
  • R.A.J. Warringa

    In vivo priming of platelet-activating factor-induced eosinophil chemotaxis in allergic asthmatic individuals

    Blood

    (1992)
  • P.C. Vincent

    The intravascular survival of neutrophils labeled in vivo

    Blood

    (1974)
  • P.S. Tofts

    Doubts concerning the recently reported human neutrophil lifespan of 5.4 days

    Blood

    (2011)
  • O. Dienz

    Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung

    Mucosal Immunol.

    (2012)
  • J.M. Adrover

    Aging: a temporal dimension for neutrophils

    Trends Immunol.

    (2016)
  • M.A. Stark

    Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17

    Immunity

    (2005)
  • E. van de Vijver

    Leukocyte adhesion deficiencies

    Hematol. Oncol. Clin. North Am.

    (2013)
  • C. Summers

    Neutrophil kinetics in health and disease

    Trends Immunol.

    (2010)
  • J. Shi

    Role of the liver in regulating numbers of circulating neutrophils

    Blood

    (2001)
  • E. Kolaczkowska et al.

    Neutrophil recruitment and function in health and inflammation

    Nat. Rev. Immunol.

    (2013)
  • P. Scapini

    Human neutrophils in the saga of cellular heterogeneity: insights and open questions

    Immunol. Rev.

    (2016)
  • J.B. Cowland et al.

    Granulopoiesis and granules of human neutrophils

    Immunol. Rev.

    (2016)
  • B.M. Babior

    The production by leukocytes of superoxide, a potential bactericidal agent

    Biol. Def. Mech.

    (1973)
  • A.W. Segal

    How neutrophils kill microbes

    Annu. Rev. Immunol.

    (2005)
  • J.T. Curnutte

    Defect in pyridine nucleotide dependent superoxide production by a particulate fraction from the granulocytes of patients with chronic granulomatous disease

    N. Engl. J. Med.

    (1975)
  • J. Kaplan

    Chediak-Higashi syndrome

    Curr. Opin. Hematol.

    (2008)
  • P.H.C. Leliefeld

    The role of neutrophils in immune dysfunction during severe inflammation

    Crit. Care

    (2016)
  • P. Hellebrekers

    Neutrophil phenotypes in health and disease

    Eur. J. Clin. Investig.

    (2018)
  • J.K. Juss

    Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-kinase inhibition

    Am. J. Respir. Crit. Care Med.

    (2016)
  • M.G. Manz

    Prospective isolation of human clonogenic common myeloid progenitors

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • S. Kawamura

    Identification of a human clonogenic progenitor with strict monocyte differentiation potential: a counterpart of mouse cMoPs

    Immunity

    (2017)
  • M. Evrard

    Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions

    Immunity

    (2018)
  • M.H. Kim

    A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis

    Sci. Rep.

    (2017)
  • C. Ramírez et al.

    Phenotypic stability and plasticity in GMP-derived cells as determined by their underlying regulatory network

    Bioinformatics

    (2018)
  • Y.P. Zhu

    Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow

    Cell Rep.

    (2018)
  • A. Olsson

    Single-cell analysis of mixed-lineage states leading to a binary cell fate choice

    Nature

    (2016)
  • J.Y. Mary

    Normal human granulopoiesis revisited. II. Bone marrow data

    Biomed. Pharmacother.

    (1985)
  • C. Dresch

    Growth fraction of myelocytes in normal human granulopoiesis

    Cell Prolif.

    (1986)
  • M.G. Manz et al.

    Emergency granulopoiesis

    Nat. Rev. Immunol.

    (2014)
  • E.P. Cronkite

    Dynamics of hemopoietic proliferation in man and mice studied by H3-thymidine incorporation into DNA

    Ann. N. Y. Acad. Sci.

    (1959)
  • J.T. Dancey

    Neutrophil kinetics in man

    J. Clin. Invest.

    (1976)
  • K.H. Steinbach

    Estimation of kinetic parameters of neutrophilic, eosinophilic, and basophilic granulocytes in human blood

    Blut

    (1979)
  • J. Arneth

    Die neutrophilen leukozyten bei infektionskrankheiten

    Dtsch. Med. Wochenschr.

    (1904)
  • T. Terashima

    Polymorphonuclear leukocyte transit times in bone marrow during streptococcal pneumonia

    Am. J. Phys.

    (1996)
  • T. Tak

    What’s your age again? Determination of human neutrophil half-lives revisited

    J. Leukoc. Biol.

    (2013)
  • Y. Orr

    A kinetic model of bone marrow neutrophil production that characterizes late phenotypic maturation

    Am. J. Physiol. Integr. Comp. Physiol.

    (2006)
  • Cited by (246)

    View all citing articles on Scopus
    View full text