Neutrophil Diversity in Health and Disease
2019; Elsevier BV; Volume: 40; Issue: 7 Linguagem: Inglês
10.1016/j.it.2019.04.012
ISSN1471-4981
AutoresCarlos Silvestre-Roig, Zvi G. Fridlender, Michael Glogauer, Patrizia Scapini,
Tópico(s)Immune Response and Inflammation
ResumoNeutrophils are the primary responders to infections and tissue damage, but a growing body of evidence suggests that distinct subpopulations of these cells are immunoregulatory and are associated with cancer and other inflammatory diseases.The source of these neutrophil subpopulations remains an open question. It is unclear if they; (i) are derived through differentiation in the bone marrow, or (ii) are generated either via activation of mature and immature neutrophils, or through changes in 'destination' tissues.The development of fieldwide and universally accepted neutrophil functional markers, as well as reproducible and simplified isolation protocols, may allow standardization of approaches to study neutrophil subpopulations. Although difficult to achieve, this may accelerate and consolidate our understanding of this challenging field. New evidence has challenged the outdated dogma that neutrophils are a homogeneous population of short-lived cells. Although neutrophil subpopulations with distinct functions have been reported under homeostatic and pathological conditions, a full understanding of neutrophil heterogeneity and plasticity is currently lacking. We review here current knowledge of neutrophil heterogeneity and diversity, highlighting the need for deep genomic, phenotypic, and functional profiling of the identified neutrophil subpopulations to determine whether these cells truly represent bona fide novel neutrophil subsets. We suggest that progress in understanding neutrophil heterogeneity will allow the identification of clinically relevant neutrophil subpopulations that may be used in the diagnosis of specific diseases and lead to the development of new therapeutic approaches. New evidence has challenged the outdated dogma that neutrophils are a homogeneous population of short-lived cells. Although neutrophil subpopulations with distinct functions have been reported under homeostatic and pathological conditions, a full understanding of neutrophil heterogeneity and plasticity is currently lacking. We review here current knowledge of neutrophil heterogeneity and diversity, highlighting the need for deep genomic, phenotypic, and functional profiling of the identified neutrophil subpopulations to determine whether these cells truly represent bona fide novel neutrophil subsets. We suggest that progress in understanding neutrophil heterogeneity will allow the identification of clinically relevant neutrophil subpopulations that may be used in the diagnosis of specific diseases and lead to the development of new therapeutic approaches. Neutrophils were thought to consist of a homogeneous population of cells that display potent antimicrobial functions including phagocytosis, degranulation, and neutrophil extracellular trap (NET) (see Glossary) production [1.Scapini P. et al.Granulocytes and mast cells.in: Paul W. Fundamental Immunology. 7th edn. Wolters Kluwer-Lippincott Williams & Wilkins, 2013: 468-486Google Scholar]. Data from the past decade have revealed that neutrophils may also exert immunoregulatory functions, as well as displaying phenotypic and functional plasticity [1.Scapini P. et al.Granulocytes and mast cells.in: Paul W. Fundamental Immunology. 7th edn. Wolters Kluwer-Lippincott Williams & Wilkins, 2013: 468-486Google Scholar, 2.Ley K. et al.Neutrophils: new insights and open questions.Sci. Immunol. 2018; 3eaat4579Crossref PubMed Scopus (5) Google Scholar]. Heterogeneous populations of circulating neutrophils have been described based on discrete parameters (e.g., cell-surface markers, buoyancy, maturity, functions, localization) both in healthy and pathological conditions including cancer, infections, and autoimmune and inflammatory disorders [3.Ng L.G. et al.Heterogeneity of neutrophils.Nat. Rev. Immunol. 2019; 19: 255-265Crossref PubMed Scopus (0) Google Scholar, 4.Chatfield S.M. et al.Expanding neutrophil horizons: new concepts in inflammation.J. Innate Immun. 2018; 10: 422-431Crossref PubMed Scopus (1) Google Scholar, 5.Christoffersson G. Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas?.Cell Tissue Res. 2018; 371: 415-423Crossref PubMed Scopus (6) Google Scholar, 6.Deniset J.F. Kubes P. Neutrophil heterogeneity: bona fide subsets or polarization states?.J. Leukoc. Biol. 2018; 103: 829-838Crossref PubMed Scopus (3) Google Scholar, 7.Garley M. Jablonska E. Heterogeneity among neutrophils.Arch. Immunol. Ther. Exp. (Warsz). 2018; 66: 21-30Crossref PubMed Scopus (7) Google Scholar, 8.Hellebrekers P. et al.Neutrophil phenotypes in health and disease.Eur. J. Clin. Investig. 2018; 48e12943Crossref PubMed Scopus (0) Google Scholar, 9.Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?.Front. Physiol. 2018; 9: 113Crossref PubMed Scopus (22) Google Scholar]. In addition, the number of studies describing the existence of tissue-based populations of neutrophils, which can be either resident or newly infiltrated, and which acquire specialized phenotypes/functions depending on the tissue microenvironment, is continuously growing [3.Ng L.G. et al.Heterogeneity of neutrophils.Nat. Rev. Immunol. 2019; 19: 255-265Crossref PubMed Scopus (0) Google Scholar, 4.Chatfield S.M. et al.Expanding neutrophil horizons: new concepts in inflammation.J. Innate Immun. 2018; 10: 422-431Crossref PubMed Scopus (1) Google Scholar, 5.Christoffersson G. Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas?.Cell Tissue Res. 2018; 371: 415-423Crossref PubMed Scopus (6) Google Scholar, 6.Deniset J.F. Kubes P. Neutrophil heterogeneity: bona fide subsets or polarization states?.J. Leukoc. Biol. 2018; 103: 829-838Crossref PubMed Scopus (3) Google Scholar, 7.Garley M. Jablonska E. Heterogeneity among neutrophils.Arch. Immunol. Ther. Exp. (Warsz). 2018; 66: 21-30Crossref PubMed Scopus (7) Google Scholar, 8.Hellebrekers P. et al.Neutrophil phenotypes in health and disease.Eur. J. Clin. Investig. 2018; 48e12943Crossref PubMed Scopus (0) Google Scholar, 9.Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?.Front. Physiol. 2018; 9: 113Crossref PubMed Scopus (22) Google Scholar]. The question of neutrophil heterogeneity is of significant interest; however, no consensus criteria and/or molecular evidence have been demonstrated to unequivocally and reproducibly define clinically relevant distinct neutrophil subsets. Therefore, whether various reported neutrophil populations consist of bona fide neutrophil subsets, or represent different states of maturation and/or activation of neutrophils exposed to disease-specific pathological conditions, remains a main open question in the field. In this review we summarize and critically discuss the most recent findings on mammalian neutrophil heterogeneity. In view of several species-specific differences that might have a profound impact on the phenotypic and functional plasticity of neutrophils, human and mouse studies are separately discussed, highlighting similarities and differences between current findings in the two species. There is emerging evidence of heterogeneous populations of neutrophils in other organisms, such as the rhesus macaque [10.Lin A. et al.Rhesus macaque myeloid-derived suppressor cells demonstrate T cell inhibitory functions and are transiently increased after vaccination.J. Immunol. 2018; 200: 286-294Crossref PubMed Scopus (6) Google Scholar], zebrafish [11.Ellett F. et al.Defining the phenotype of neutrophils following reverse migration in zebrafish.J. Leukoc. Biol. 2015; 98: 975-981Crossref PubMed Scopus (0) Google Scholar, 12.Huo X. et al.Transcriptomic profiles of tumor-associated neutrophils reveal prominent roles in enhancing angiogenesis in liver tumorigenesis in zebrafish.Sci. Rep. 2019; 9: 1509Crossref PubMed Scopus (0) Google Scholar], and horse [13.Herteman N. et al.Characterization of circulating low-density neutrophils intrinsic properties in healthy and asthmatic horses.Sci. Rep. 2017; 7: 7743Crossref PubMed Scopus (4) Google Scholar], but these are beyond the scope of our discussion. Several publications have reported that, in healthy individuals, 45–65% of circulating neutrophils are CD177+ [5.Christoffersson G. Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas?.Cell Tissue Res. 2018; 371: 415-423Crossref PubMed Scopus (6) Google Scholar, 6.Deniset J.F. Kubes P. Neutrophil heterogeneity: bona fide subsets or polarization states?.J. Leukoc. Biol. 2018; 103: 829-838Crossref PubMed Scopus (3) Google Scholar, 8.Hellebrekers P. et al.Neutrophil phenotypes in health and disease.Eur. J. Clin. Investig. 2018; 48e12943Crossref PubMed Scopus (0) Google Scholar, 14.Silvestre-Roig C. et al.Neutrophil heterogeneity: implications for homeostasis and pathogenesis.Blood. 2016; 127: 2173-2181Crossref PubMed Google Scholar], with variability of CD177 expression reflecting control by epigenetic mechanisms [15.Eulenberg-Gustavus C. et al.Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets.J. Exp. Med. 2017; 214: 2089-2101Crossref PubMed Scopus (7) Google Scholar] (Figure 1). CD177 (also known as human neutrophil antigen NB1) is a glycoprotein expressed on the plasma membrane and within specific granules of neutrophils. It is known to promote the interaction of neutrophils with endothelial cells, as well as their transmigration out of the vasculature, by binding to platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) [16.Sachs U.J. et al.The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31).J. Biol. Chem. 2007; 282: 23603-23612Crossref PubMed Scopus (0) Google Scholar] or β2 integrins [17.Bai M. et al.CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation.Blood. 2017; 130: 2092-2100Crossref PubMed Scopus (14) Google Scholar]. Because CD177 also serves as a receptor of membrane-bound proteinase 3, a major antigen targeted by antineutrophil cytoplasmic antibodies (ANCAs), the association between expression of CD177 and susceptibility to develop (ANCA)-associated systemic vasculitis is under investigation [18.Deng H. et al.Interaction between CD177 and platelet endothelial cell adhesion molecule-1 downregulates membrane-bound proteinase-3 (PR3) expression on neutrophils and attenuates neutrophil activation induced by PR3–ANCA.Arthritis Res. Ther. 2018; 20: 213Crossref PubMed Scopus (0) Google Scholar, 19.Jerke U. et al.Characterization of the CD177 interaction with the ANCA antigen proteinase 3.Sci. Rep. 2017; 743328Crossref PubMed Scopus (5) Google Scholar, 20.von Vietinghoff S. et al.NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils.Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (86) Google Scholar]. Similarly to the CD177+ neutrophil population, only a small proportion (~20–25%) of circulating mature neutrophils in healthy subjects express the glycoprotein olfactomedin 4 (OLFM4) that is contained within specific neutrophilic granules [21.Clemmensen S.N. et al.Olfactomedin 4 defines a subset of human neutrophils.J. Leukoc. Biol. 2012; 91: 495-500Crossref PubMed Scopus (0) Google Scholar] (Figure 1). The specific function of this protein in neutrophils is still unknown. Indeed, whether OLFM4+ neutrophils represent a real distinct functional population remains unclear because OLFM4+ and OLFM4− neutrophils do not display major functional differences other than a differential ability to produce NETs in vitro [22.Welin A. et al.The human neutrophil subsets defined by the presence or absence of OLFM4 both transmigrate into tissue in vivo and give rise to distinct NETs in vitro.PLoS One. 2013; 8e69575Crossref PubMed Scopus (0) Google Scholar]. Notably, the frequency of OLFM4+ neutrophils is increased in sepsis relative to healthy conditions [23.Alder M.N. et al.Olfactomedin-4 is a candidate marker for a pathogenic neutrophil subset in septic shock.Crit. Care Med. 2017; 45: e426-e432Crossref PubMed Scopus (1) Google Scholar], whereas the frequency of circulating CD177+ neutrophils is increased in other inflammatory diseases including asthma [24.Ramirez-Velazquez C. et al.IL-17-producing peripheral blood CD177+ neutrophils increase in allergic asthmatic subjects.Allergy Asthma Clin. Immunol. 2013; 9: 23Crossref PubMed Scopus (34) Google Scholar], sepsis [25.Demaret J. et al.Identification of CD177 as the most dysregulated parameter in a microarray study of purified neutrophils from septic shock patients.Immunol. Lett. 2016; 178: 122-130Crossref PubMed Scopus (5) Google Scholar, 26.Schreiber A. et al.CD177/NB1 receptor expression is dynamically regulated in sepsis patients.Immunohematology. 2015; 31: 128-129PubMed Google Scholar], cancer [27.Zhou G. et al.CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer.Carcinogenesis. 2018; 39: 272-282Crossref PubMed Scopus (3) Google Scholar], and inflammatory bowel disease [28.Zhou G. et al.CD177+ neutrophils as functionally activated neutrophils negatively regulate IBD.Gut. 2018; 67: 1052-1063Crossref PubMed Scopus (9) Google Scholar]. It is important to note that, although the presence of these subpopulations has been reported in several studies, a deeper understanding of the specific functions of these cells will be necessary to determine their prognostic or therapeutic clinical value. Other studies have suggested, based on differential expression of selected markers, that other circulating neutrophil subpopulations, for example, those expressing the T cell receptor αβ (TCRαβ)+ [29.Puellmann K. et al.A variable immunoreceptor in a subpopulation of human neutrophils.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 14441-14446Crossref PubMed Scopus (0) Google Scholar] or proangiogenic CD49d+CXCR4+vascular endothelial growth factor (VEGFR1)+ [30.Massena S. et al.Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans.Blood. 2015; 126: 2016-2026Crossref PubMed Scopus (66) Google Scholar], are present in healthy individuals, but these observations remain to be further validated. Neutrophil ontogeny is currently recognized as a major contributor to heterogeneity [3.Ng L.G. et al.Heterogeneity of neutrophils.Nat. Rev. Immunol. 2019; 19: 255-265Crossref PubMed Scopus (0) Google Scholar, 8.Hellebrekers P. et al.Neutrophil phenotypes in health and disease.Eur. J. Clin. Investig. 2018; 48e12943Crossref PubMed Scopus (0) Google Scholar, 9.Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?.Front. Physiol. 2018; 9: 113Crossref PubMed Scopus (22) Google Scholar]. Because of its rapid homeostatic turnover, the size of the circulating mature neutrophil pool is maintained by a fine balance between granulopoiesis, neutrophil release from the bone marrow (BM) into the circulation, and ultimately return to the BM for final clearance by resident macrophages [31.Lawrence S.M. et al.The ontogeny of a neutrophil: mechanisms of granulopoiesis and homeostasis.Microbiol. Mol. Biol. Rev. 2018; 82 (e00057-17)Crossref PubMed Scopus (4) Google Scholar] (Figure 1). Although the latter process has been better characterized in mice (see below), there is also evidence for neutrophil recycling and destruction within the human BM [32.Szczepura K.R. et al.Measuring whole-body neutrophil redistribution using a dedicated whole-body counter and ultra-low doses of 111Indium.Eur. J. Clin. Investig. 2011; 41: 77-83Crossref PubMed Scopus (8) Google Scholar]. Currently, there is renewed interest in better understanding the sequential steps of neutrophil maturation [33.Evrard M. et al.Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions.Immunity. 2018; 48: 364-379Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 34.Zhu Y.P. et al.Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow.Cell Rep. 2018; 24: 2329-2341Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], as well as the transcriptomic and epigenomic programs they carry [35.Grassi L. et al.Dynamics of transcription regulation in human bone marrow myeloid differentiation to mature blood neutrophils.Cell Rep. 2018; 24: 2784-2794Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], and through which these granulocytes progressively acquire specific functional abilities. Further complicating our understanding of neutrophil identities, the phenotype of circulating mature neutrophils appears to vary over the course of their lifespan [3.Ng L.G. et al.Heterogeneity of neutrophils.Nat. Rev. Immunol. 2019; 19: 255-265Crossref PubMed Scopus (0) Google Scholar, 6.Deniset J.F. Kubes P. Neutrophil heterogeneity: bona fide subsets or polarization states?.J. Leukoc. Biol. 2018; 103: 829-838Crossref PubMed Scopus (3) Google Scholar, 8.Hellebrekers P. et al.Neutrophil phenotypes in health and disease.Eur. J. Clin. Investig. 2018; 48e12943Crossref PubMed Scopus (0) Google Scholar, 9.Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?.Front. Physiol. 2018; 9: 113Crossref PubMed Scopus (22) Google Scholar]. Similarly to what has been consistently published in papers utilizing mouse models (see below), diurnal oscillations of C-X-C chemokine receptor type 4 (CXCR4) expression have been found in circulating neutrophils from healthy subjects, and these were proposed to correlate with neutrophil maturation and aging [36.Ella K. et al.Circadian regulation of human peripheral neutrophils.Brain Behav. Immun. 2016; 57: 209-221Crossref PubMed Scopus (15) Google Scholar, 37.Adrover J.M. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50: 390-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Moreover, as shown by flow cytometry analysis performed at different times of the day, the proportion of CXCR4−CD62L+ young and CXCR4+CD62L− aged neutrophil populations among circulating neutrophils from healthy individuals has been shown to be regulated by circadian oscillations [37.Adrover J.M. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50: 390-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] (Figure 1). Naïve tissues were traditionally considered to be devoid of neutrophils in the absence of inflammatory insults. However, recent findings from mice (see below) have revealed the existence of neutrophil pools that, under homeostatic conditions, reside in the spleen and liver, in addition to the BM [3.Ng L.G. et al.Heterogeneity of neutrophils.Nat. Rev. Immunol. 2019; 19: 255-265Crossref PubMed Scopus (0) Google Scholar, 5.Christoffersson G. Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas?.Cell Tissue Res. 2018; 371: 415-423Crossref PubMed Scopus (6) Google Scholar, 6.Deniset J.F. Kubes P. Neutrophil heterogeneity: bona fide subsets or polarization states?.J. Leukoc. Biol. 2018; 103: 829-838Crossref PubMed Scopus (3) Google Scholar, 9.Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?.Front. Physiol. 2018; 9: 113Crossref PubMed Scopus (22) Google Scholar]. In this context, although this finding remains controversial [38.Nagelkerke S.Q. et al.Failure to detect functional neutrophil B helper cells in the human spleen.PLoS One. 2014; 9e88377Crossref PubMed Scopus (0) Google Scholar], a human splenic neutrophil subpopulation that resides within the splenic marginal zone (MZ) has been defined as 'B cell helper neutrophils' (NBH cells) based on their unique ability to promote B cell proliferation and antibody production, and which is absent from resting circulating neutrophils [39.Puga I. et al.B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen.Nat. Immunol. 2011; 13: 170-180Crossref PubMed Scopus (266) Google Scholar] (Figure 1). Overall, further research will be necessary to gain a better understanding of the phenotypic and functional features of reported neutrophil subpopulations in the circulation and tissues of healthy individuals. The expression of surface glycoproteins, such as CD177 or OLMF4, that in humans has been thought to define distinct neutrophil subpopulations, is also present in mice in different proportions [14.Silvestre-Roig C. et al.Neutrophil heterogeneity: implications for homeostasis and pathogenesis.Blood. 2016; 127: 2173-2181Crossref PubMed Google Scholar, 40.Alder M.N. et al.Olfactomedin 4 marks a subset of neutrophils in mice.Innate Immun. 2018; 25: 22-33Crossref PubMed Scopus (0) Google Scholar] (Figure 1); however, their functional relevance remains unknown. Of note, a mouse neutrophil subpopulation defined as CD49d+CXCR4+VEGFR1+ and proangiogenic [30.Massena S. et al.Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans.Blood. 2015; 126: 2016-2026Crossref PubMed Scopus (66) Google Scholar] has been described elsewhere [5.Christoffersson G. Phillipson M. The neutrophil: one cell on many missions or many cells with different agendas?.Cell Tissue Res. 2018; 371: 415-423Crossref PubMed Scopus (6) Google Scholar]. Developmental analysis of neutrophil populations within the mouse BM has instead revealed the existence of subpopulations of proliferative precursors as well as immature and mature neutrophils (similar to their circulating counterparts), and these have also been proposed to be present in humans (see above) (Figure 1); these subpopulations display different expansion and effector activities under microbial and tumoral stress [33.Evrard M. et al.Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions.Immunity. 2018; 48: 364-379Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 34.Zhu Y.P. et al.Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow.Cell Rep. 2018; 24: 2329-2341Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Indeed, although mature neutrophils were found to be essential for antimicrobial host defense in a mouse model of cecal ligation and puncture (CLP)-induced sepsis [33.Evrard M. et al.Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions.Immunity. 2018; 48: 364-379Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar], neutrophil precursors were able to expand and support granulopoiesis in CLP [33.Evrard M. et al.Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions.Immunity. 2018; 48: 364-379Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar], as well as in pancreatic [33.Evrard M. et al.Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions.Immunity. 2018; 48: 364-379Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar] and melanoma [34.Zhu Y.P. et al.Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow.Cell Rep. 2018; 24: 2329-2341Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] tumor mouse models; in the latter models, neutrophil precursors could also promote tumor growth by exerting T cell-mediated immunosuppression via programmed death ligand 1 (PD-L1/CD274)-dependent mechanisms [34.Zhu Y.P. et al.Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow.Cell Rep. 2018; 24: 2329-2341Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Similarly, the neutrophil 'aging' process is better documented in mice than in humans. After mobilization from the BM, circulating aged neutrophils upregulate CXCR4 and CD11b, and lose CD62L, before homing back to the BM, spleen, or liver for clearance [37.Adrover J.M. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50: 390-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 41.Casanova-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 (201) Google Scholar] (Figure 1). Aged neutrophils are also retained in the lung, where they become apoptotic by interacting with B cells, a process that precedes their clearance by tissue-resident macrophages [42.Kim J.H. et al.Aged polymorphonuclear leukocytes cause fibrotic interstitial lung disease in the absence of regulation by B cells.Nat. Immunol. 2018; 19: 192-201Crossref PubMed Scopus (1) Google Scholar]. In this mouse model, B cell depletion reduced apoptosis of aged neutrophils which then accumulated in the lung and induced interstitial inflammation and fibrosis [42.Kim J.H. et al.Aged polymorphonuclear leukocytes cause fibrotic interstitial lung disease in the absence of regulation by B cells.Nat. Immunol. 2018; 19: 192-201Crossref PubMed Scopus (1) Google Scholar]. Of note, this aging process is necessary for the circadian control of hematopoietic niche function and progenitor mobilization [41.Casanova-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 (201) Google Scholar], while also enhancing neutrophil antimicrobial activity during host defense in a mouse model of Candida albicans infection [37.Adrover J.M. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50: 390-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Thus, neutrophil aging can favor migration to the tissue at night-time, and enhance the antimicrobial properties of neutrophils at the time of the day when mice are exposed to pathogens. Mechanistically, antibiotic treatment or mice deficient in Toll-like receptors (TLRs) 2 or 4 showed reduced numbers of aged neutrophils relative to controls, suggesting that microbiome signals transduced through TLRs could promote neutrophil aging [43.Zhang D. et al.Neutrophil ageing is regulated by the microbiome.Nature. 2015; 525: 528-532Crossref PubMed Scopus (171) Google Scholar]. Moreover, owing to their increased inflammatory activity, accumulated aged neutrophils have also been reported to promote vascular damage and disease; for instance, relative to controls, they contributed to increasing infarction size lesions and vaso-occlusion in mouse models of myocardial infarction and sickle cell disease, respectively [37.Adrover J.M. et al.A neutrophil timer coordinates immune defense and vascular protection.Immunity. 2019; 50: 390-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43.Zhang D. et al.Neutrophil ageing is regulated by the microbiome.Nature. 2015; 525: 528-532Crossref PubMed Scopus (171) Google Scholar]. Finally, as shown in multiple mouse studies, there is strong evidence that, in the absence of inflammatory insults, neutrophils are not necessarily confined to the BM, blood, and margination sites (mostly the lungs and spleen), but are able to transit into, and remain in, many tissues where they might exert organ-specific functions [44.Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (0) Google Scholar] (Figure 1). Perhaps consistent with specialized macrophages residing in the liver or brain (i.e., Kupffer cells or microglia) [45.Gordon S. et al.Macrophage heterogeneity in tissues: phenotypic diversity and functions.Immunol. Rev. 2014; 262: 36-55Crossref PubMed Scopus (217) Google Scholar], it is reasonable to speculate that there may also be specialized resident neutrophils within other tissues or sites, although this remains to be investigated. Regarding function, intestinal CD169+ macrophage-mediated neutrophil phagocytosis has been shown to reduce the production of interleukin (IL)-23 and lower the secretion of granulocyte colony-stimulating factor (G-CSF), thus distally controlling granulopoiesis within the BM [44.Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (0) Google Scholar]. In the lung, neutrophil infiltration could alter the circadian regulation of gene transcription as well as the susceptibility to develop metastasis in tumor mouse models [44.Casanova-Acebes M. et al.Neutrophils instruct homeostatic and pathological states in naive tissues.J. Exp. Med. 2018; 215: 2778-2795Crossref PubMed Scopus (0) Google Scholar]. Of note, mass cytometry analysis of multiple tissues has shown that, of all myeloid subsets, neutrophils display the highest degree of heterogeneity [46.Becher B. et al.High-dimensional analysis of the murine myeloid cell system.Nat. Immunol. 2014; 15: 1181-1189Crossref PubMed Scopus (166) Google Scholar], supporting the concept that specialized neutrophils are present within different organs. For instance, in line with observations in human samples, splenic MZ-residing neutrophils constitute a subpopulation harboring a specific ability to regulate B cell responses, mostly via secretion of soluble pentraxin 3 during homeostasis as well as during Streptococcus pneumonia infection [47.Chorny A. et al.The
Referência(s)