Neutrophil phenotypes in health and disease

Pien Hellebrekers, Nienke Vrisekoop, Leo Koenderman, Pien Hellebrekers, Nienke Vrisekoop, Leo Koenderman

Abstract

Neutrophils are one of the most important effector cells of the innate immune response (1). They are traditionally seen as a homogenous population of short-lived cells mainly involved in the defence against extracellular microorganisms by phagocytosis and intracellular killing (1,2). The cells contain a large armamentarium that aids in this function and ranges from the production of reactive oxygen species by a membrane-bound NADPH oxidase to cytotoxic proteins and peptides residing in the different granules present in the cytoplasm (3). Recently, the view of neutrophils belonging to a homogenous population of cells has been challenged, and several neutrophil phenotypes have been described that exhibit specialized functions, such as involvement in tissue repair, tumour killing and immune regulation (4). It is not clear whether these cells belong to separate parallel lineages originating from the bone marrow or that neutrophils become instructed in the distant tissues, thus changing their phenotypes. In addition, functional heterogeneity in a phenotypically homogenous population of neutrophils adds to the complexity of neutrophil phenotypes(5). This article will review the current literature describing the heterogeneity within the neutrophil compartment with respect to both phenotype and function in health and disease.

Keywords: challenge; immune; immune regulation; inflammation; neutrophil; origin; phenotype.

© 2018 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

Figures

Figure 1
Figure 1
Neutrophil phenotypes in health and disease. Neutrophils develop in the bone marrow and leave the bone marrow after 5‐6 days.20 The cells circulate as a homogeneous population in the peripheral blood and can go to the tissues in small numbers under homeostatic conditions. In disease, neutrophil phenotypes redistribute and are present in peripheral blood and distant tissues. The origin of at least part of the additional blood neutrophil phenotypes remains to be established

References

    1. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33:657‐670.
    1. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER. Neutrophil kinetics in health and disease. Trends Immunol. 2010;31:318‐324.
    1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:159‐175.
    1. Silvestre‐Roig C, Hidalgo A, Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood. 2016;127:2173‐2181.
    1. Hellebrekers P, Hietbrink F, Vrisekoop N, Leenen LPH, Koenderman L. Neutrophil functional heterogeneity: identification of competitive phagocytosis. Front Immunol. 2017;8:1‐9.
    1. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012;30:459‐489.
    1. Hallett MB, Lloyds D. Neutrophil priming: the cellular signals that say “amber” but not “green”. Immunol Today. 1995;16:264‐268.
    1. Lyck R, Enzmann G. The physiological roles of ICAM‐1 and ICAM‐2 in neutrophil migration into tissues. Curr Opin Hematol. 2015;22:53‐59.
    1. Margadant C, Monsuur HN, Norman JC, Sonnenberg A. Mechanisms of integrin activation and trafficking. Curr Opin Cell Biol. 2011;23:607‐614.
    1. Foxman EF, Campbell JJ, Butcher EC. Multistep navigation and the combinatorial control of leukocyte chemotaxis. J Cell Biol. 1997;139:1349‐1360.
    1. Ferrante A, Martin AJ, Bates EJ, et al. Killing of Staphylococcus aureus by tumor necrosis factor‐alpha‐activated neutrophils. The role of serum opsonins, integrin receptors, respiratory burst, and degranulation. J Immunol. 1993;151:4821‐4828.
    1. Kumaratilake LM, Ferrante A, Jaeger T, Rzepczyk C. GM‐CSF‐induced priming of human neutrophils for enhanced phagocytosis and killing of asexual blood stages of Plasmodium falciparum: synergistic effects of GM‐CSF and TNF. Parasite Immunol. 1996;18:115‐123.
    1. Bajaj MS, Kew RR, Webster RO, Hyers TM. Priming of human neutrophil functions by tumor necrosis factor: enhancement of superoxide anion generation, degranulation, and chemotaxis to chemoattractants C5a and f‐Met‐Leu‐Phe. Inflammation. 1992;16:241‐250.
    1. Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197‐223.
    1. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532‐1535.
    1. Davis JM, Albert JD, Tracy KJ, et al. Increased neutrophil mobilization and decreased chemotaxis during cortisol and epinephrine infusions. J Trauma. 1991;31:725‐732.
    1. Athens JW, Raab SO, Mauer AM, Ashenbrucker H, Cartwright GE, Wintrobe MM. Leukokinetic studies IV. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. J Clin Invest. 1961;40:989‐995.
    1. Phillips D, Rezvani K, Bain BJ. Exercise induced mobilisation of the marginated granulocyte pool in the investigation of ethnic neutropenia. J Clin Pathol. 2000;53:481‐483.
    1. Seebach JD, Morant R, Rüegg R, Seifert B, Fehr J. The diagnostic value of the neutrophil left shift in predicting inflammatory and infectious diseases. Am J Clin Pathol. 1997;107:582‐591.
    1. Tak T, Wijten P, Heeres M, et al. Human CD62L dim neutrophils identified as a separate subset by proteome profiling and in vivo pulse‐chase labeling. Blood. 2018;129:3476‐3486.
    1. Thompson W, Cassino C, Babitz L, et al. Hypersegmented neutrophils and vitamin B12 deficiency. Hypersegmentation in B12 deficiency. Acta Haematol. 1989;81:186‐191.
    1. Orr Y, Taylor JM, Bannon PG, Geczy C, Kritharides L. Circulating CD10‐/CD16low neutrophils provide a quantitative index of active bone marrow neutrophil release. Br J Haematol. 2005;131:508‐519.
    1. van Lochem EG, van der Velden VHJ, Wind HK, te Marvelde JG, Westerdaal NAC, van Dongen JJM. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age‐related changes and disease‐induced shifts. Cytometry. 2004;60B:1‐13.
    1. Ssemaganda A, Kindinger L, Bergin P, et al. Characterization of neutrophil subsets in healthy human pregnancies. PLoS One. 2014;9:e85696.
    1. Uhl B, Vadlau Y, Zuchtriegel G, et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016;128:2327‐2338.
    1. Greenlee‐wacker MC. Clearance of apoptotic neutrophils and resolution of inflammation. Immunol Rev. 2016;273:357‐370.
    1. Casanova‐Acebes M, Pitaval C, Weiss LA, et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell. 2013;153:1025‐1035.
    1. Pillay J, Den Braber I, Vrisekoop N, et al. In vivo labeling with 2‐H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116:625‐627.
    1. Lahoz‐Beneytez J, Elemans M, Zhang Y, et al. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half‐lives. Blood. 2016;127:3431‐3438.
    1. Tak T, Tesselaar K, Pillay J, Borghans JAM, Koenderman L. What's your age again? determination of human neutrophil half‐lives revisited. J Leukoc Biol. 2013;94:595‐601.
    1. Nagaraj S, Gabrilovich DI. Myeloid‐derived suppressor cells. Adv Exp Med Biol. 2007;601:213‐223.
    1. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor‐associated neutrophil phenotype by TGF‐β: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183‐194.
    1. Pillay J, Tak T, Kamp VM, Koenderman L. Immune suppression by neutrophils and granulocytic myeloid‐derived suppressor cells: similarities and differences. Cell Mol Life Sci. 2013;70:3813‐3827.
    1. Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166:678‐689.
    1. Youn J‐I, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid‐derived suppressor cells in tumor‐bearing mice. J Leukoc Biol. 2012;91:167‐181.
    1. Youn J‐I, Gabrilovich DI. The biology of myeloid‐derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010;40:2969‐2975.
    1. Highfill SL, Rodriguez PC, Zhou Q, et al. Bone marrow myeloid‐derived suppressor cells (MDSC) inhibit graft‐versus‐host (GVHD) disease via an arginase‐1 dependent mechanism that is upregulated by IL‐13. Blood. 2010;116:612‐626.
    1. Wu H, Zhen Y, Ma Z, et al. Arginase‐1‐dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci Transl Med. 2016;8:1‐10.
    1. Albanesi M, Mancardi D, Jönsson F, et al. Neutrophils mediate antibody‐induced antitumor effects in mice. Blood. 2013;122:3160‐3164.
    1. Valgardsdottir R, Cattaneo I, Klein C, Introna M, Figliuzzi M, Golay J. Human neutrophils mediate trogocytosis rather than phagocytosis of CLL B cells opsonized with anti‐CD20 antibodies. Blood. 2017;129:2636‐2644.
    1. Shen M, Hu P, Donskov F, Wang G, Liu Q, Du J. Tumor‐associated neutrophils as a new prognostic factor in cancer: a systematic review and meta‐analysis. PLoS One. 2014;9:e98259.
    1. Pillay J, Kamp VM, Van Hoffen E, et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac‐1. J Clin Invest. 2012;122:327‐336.
    1. Marini O, Costa S, Bevilacqua D, et al. Mature CD10+ and immature CD10‐ neutrophils present in G‐CSF – treated donors display opposite effects on T cells. Blood. 2017;129:1343‐1357.
    1. Geng S, Matsushima H, Okamoto T, et al. Emergence, origin, and function of neutrophil‐dendritic cell hybrids in experimentally induced inflammatory lesions in mice. Blood. 2013;121:1690‐1700.
    1. Carmona‐Rivera C, Kaplan MJ. Low‐density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol. 2013;35:455‐463.
    1. Denny MF, Yalavarthi S, Zhao W, et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. 2010;184:3284‐3297.
    1. Peters T, Sindrilaru A, Hinz B, et al. Wound‐healing defect of CD18‐/‐ mice due to a decrease in TGF‐beta1 and myofibroblast differentiation. EMBO J. 2005;24:3400‐3410.
    1. Schruefer R, Sulyok S, Schymeinsky J, Peters T, Scharffetter‐Kochanek K, Walzog B. The proangiogenic capacity of polymorphonuclear neutrophils delineated by microarray technique and by measurement of neovascularization in wounded skin of CD18‐deficient mice. J Vasc Res. 2006;43:1‐11.
    1. Wada T, Tone Y, Shibata F, Toma T, Yachie A. Delayed wound healing in leukocyte adhesion deficiency type 1. J Pediatr. 2011;158:342.
    1. Etzioni A, Tonetti M. Leukocyte adhesion deficiency II‐from A to almost Z. Immunol Rev. 2000;178:138‐147.
    1. Kinashi T, Aker M, Sokolovsky‐Eisenberg M, et al. LAD‐III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood. 2004;103:1033‐1036.
    1. Bastian OW, Koenderman L, Alblas J, Leenen LPH, Blokhuis TJ. Neutrophils contribute to fracture healing by synthesizing fibronectin+extracellular matrix rapidly after injury. Clin Immunol. 2016;164:78‐84.
    1. Grundnes O, Reikeras O. The importance of the hematoma in fracture healing. Acta Orthop Scand. 1993;64:340‐342.
    1. Bastian OW, Kuijer A, Koenderman L, et al. Impaired bone healing in multitrauma patients is associated with altered leukocyte kinetics after major trauma. J Inflamm Res. 2016;9:69‐78.
    1. Massena S, Christoffersson G, Evelina V, et al. Identification and characterization of VEGF‐A – responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood. 2016;126:2016‐2027.
    1. Christoffersson G, Vågesjö E, Vandooren J, et al. VEGF‐A recruits a proangiogenic MMP‐9–delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue VEGF‐A recruits a proangiogenic MMP‐9 – delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood. 2013;120:4653‐4662.
    1. Mishalian I, Bayuh R, Levy L, Zolotarov L, Michaeli J, Fridlender ZG. Tumor‐associated neutrophils (TAN) develop pro‐tumorigenic properties during tumor progression. Cancer Immunol Immunother. 2013;62:1745‐1756.
    1. Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:593‐601.
    1. Kang EM, Marciano BE, Deravin S, Zarember KA, Holland SM, Malech HL. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011;127:1319‐1326.
    1. Lord JM, Midwinter MJ, Chen YF, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384:1455‐1465.
    1. Hoenderdos K, Condliffe A. The neutrophil in chronic obstructive pulmonary disease: too little, too late or too much, too soon? Am J Respir Cell Mol Biol. 2013;48:531‐539.
    1. Graff I, Schram‐Doumont A, Szpirer C. Defective protein kinase C‐mediated actions in cystic fibrosis neutrophils. Cell Signal. 1991;3:259‐266.
    1. Fujishima S, Aikawa N. Neutrophil‐mediated tissue injury and its modulation. Intensive Care Med. 1995;21:277‐285.
    1. Yago T, Petrich BG, Zhang N, et al. Blocking neutrophil integrin activation prevents ischemia–reperfusion injury. J Exp Med. 2015;212:1267‐1281.
    1. Bruijnzeel PLB, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease‐relevant neutrophil phenotype? J Leukoc Biol. 2015;98:549‐556.
    1. Roos D, Kuhns DB, Maddalena A, et al. Hematologically important mutations: X‐linked chronic granulomatous disease (third update). Blood Cells Mol Dis. 2010;45:246‐265.
    1. van de Geer A, Gazendam RP, Kuijpers TW, Roos D. Neutrophil functional disorders. In: eLS. Chichester: John Wiley & Sons, Ltd; 2017. 10.1002/9780470015902.a0002182.pub3
    1. Pories SE, Gamelli RL, Mead PB, Goodwin G, Harris F, Vacek P. The epidemiologic features of nosocomial infections in patients with trauma. Arch Surg. 1991;126:97‐99.
    1. Hietbrink F, Koenderman L, Althuizen M, Pillay J, Kamp V, Leenen LPH. Kinetics of the innate immune response after trauma. Shock. 2013;40:21‐27.
    1. Groeneveld KM, Koenderman L, Warren BL, Jol S, Leenen LPH, Hietbrink F. Early decreased neutrophil responsiveness is related to late onset sepsis in multitrauma patients: an international cohort study. PLoS One. 2017;12:e0180145.
    1. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72:1491‐1501.
    1. Vanzant EL, Lopez CM, Ozrazgat‐Baslanti T, et al. Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J Trauma Acute Care Surg. 2014;76:21‐30.
    1. Mira JC, Brakenridge SC, Moldawer LL, Moore FA. Persistent inflammation, immunosuppression and catabolism syndrome. Crit Care Clin. 2017;33:245‐258.
    1. Thompson AB, Robbins RA, Ghafouri MA, Linder J, Rennard SI. Bronchoalveolar lavage fluid processing. Effect of membrane filtration preparation on neutrophil recovery. Acta Cytol. 1989;33:544‐549.
    1. Gupta V, Singh D. Critical assessment of the value of sputum neutrophils. COPD. 2013;10:107‐114.
    1. Watson F, Robinson JJ, Phelan M, Bucknall RC, Edwards SW. Receptor expression in synovial fluid neutrophils from patients with rheumatoid arthritis. Ann Rheum Dis. 1993;52:354‐359.
    1. Ashkenazi M, Dennison DK. A new method for isolation of salivary neutrophils and determination of their functional activity. J Dent Res. 1989;68:1256‐1261.
    1. Fortunati E, Kazemier KM, Grutters JC, Koenderman L, Van Den Bosch VJMM. Human neutrophils switch to an activated phenotype after homing to the lung irrespective of inflammatory disease. Clin Exp Immunol. 2009;155:559‐566.
    1. Ma Y, Yabluchanskiy A, Iyer RP, et al. Temporal neutrophil polarization following myocardial infarction. Cardiovasc Res. 2016;110:51‐61.
    1. Stroncek DF, Shankar RA, Noren PA, Herr GP, Clement LT. Analysis of the expression of NB1 antigen using two monocloncal antibodies. Transfusion. 1996;36:168‐174.
    1. Sachs UJ, Andrei‐Selmer CL, Maniar A, et al. The neutrophil‐specific antigen CD177 is a counter‐receptor for platelet endothelial cell adhesion molecule‐1(CD31). J Biol Chem. 2007;282:23603‐23612.
    1. Bai M, Grieshaber‐Bouyer R, Wang J, et al. CD177 modulates human neutrophil migration through activation‐mediated integrin and chemoreceptor regulation. Blood. 2017;130:2092‐2100.
    1. Jerke U, Rolle S, Dittmar G, et al. Complement receptor Mac‐1 is an adaptor for NB1 (CD177)‐mediated PR3‐ANCA neutrophil activation. J Biol Chem. 2011;286:7070‐7081.
    1. Clemmensen SN, Bohr CT, Rorvig S, et al. Olfactomedin 4 defines a subset of human neutrophils. J Leukoc Biol. 2012;91:495‐500.
    1. Liu W, Yan M, Liu Y, McLeish KR, Coleman WG, Rodgers GP. Olfactomedin 4 inhibits cathepsin C‐mediated protease activities, thereby modulating neutrophil killing of Staphylococcus aureus and Escherichia coli in mice. J Immunol. 2012;189:2460‐2467.
    1. Liu W, Yan M, Sugui JA, et al. Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease. J Clin Invest. 2013;123:3751‐3755.
    1. Liu W, Li H, Hong SH, Piszczek GP, Chen W, Rodgers GP. Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+mice. Oncogene. 2016;35:5237‐5247.
    1. Alder MN, Opoka AM, Lahni P, Hildeman DA, Wong HR. Olfactomedin‐4 Is a candidate marker for a pathogenic neutrophil subset in septic shock. Crit Care Med. 2017;45:e426‐e432.
    1. Guette C, Valo I, Vétillard A, Coqueret O. Olfactomedin‐4 is a candidate biomarker of solid gastric, colorectal, pancreatic, head and neck, and prostate cancers. Proteomics Clin Appl. 2015;9:58‐63.
    1. Liu W, Rodgers GP. Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer. Cancer Metastasis Rev. 2016;35:201‐212.
    1. Johansson MW. Activation states of blood eosinophils in asthma. Clin Exp Allergy. 2014;44:482‐498.
    1. Leentjens J, Kox M, Koch RM, et al. Reversal of immunoparalysis in humans in vivo: a double‐blind, placebo‐controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186:838‐845.

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