Home LiteratureArticle Details
PMID: 22064428 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Review

The neutrophil in vascular inflammation.

Nature medicine ·Vol. 17 ·No. 11 ·2011-11-07 ·Pages 1381-90

Phillipson M, Kubes P

Abstract

Here we focus on how neutrophils have a key regulatory role in vascular inflammation. Recent studies using advanced imaging techniques have yielded new insights into the mechanisms by which neutrophils contribute to defense against bacterial infections and also against sterile injury. In these settings, neutrophils are recruited by various mechanisms depending on the situation. We also describe how these processes may be disrupted in systemic infections, with a particular emphasis on mouse models of sepsis. Neutrophils are often immobilized in the lungs and liver during systemic infections, and this immobilization may be a mechanism through which bacteria can evade the innate immune response or allow neutrophils to form neutrophil extracellular traps that trap and kill bacteria in blood. The platelet is also an important player in sepsis, and we describe how it collaborates with neutrophils in the formation of neutrophil extracellular traps.

MeSH Terms
Bacteria/immunology,pathogenicity Bacterial Infections/immunology Blood Vessels/immunology,pathology Chemotaxis, Leukocyte Humans Neutrophil Activation Neutrophils/cytology,immunology,physiology PTEN Phosphohydrolase/metabolism Phosphatidylinositol 3-Kinases/metabolism Vasculitis/immunology,pathology p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
Phosphatidylinositol 3-Kinases p38 Mitogen-Activated Protein Kinases PTEN Phosphohydrolase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Phillipson Mia
Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden.
Kubes Paul
References (97)
97 references, click to expand
  1. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps.
    Cell Death Differ. 2009 Nov;16(11):1438-44 PMID: 19609275
  2. Net inflammatory capacity of human septic shock plasma evaluated by a monocyte-based target cell assay: identification of interleukin-10 as a major functional deactivator of human monocytes.
    J Exp Med. 1996 Jul 1;184(1):51-60 PMID: 8691149
  3. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20262-7 PMID: 18077379
  4. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis.
    Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4018-23 PMID: 19234125
  5. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.
    J Clin Invest. 1995 Jul;96(1):60-8 PMID: 7542286
  6. Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice.
    J Exp Med. 1997 Oct 20;186(8):1357-64 PMID: 9334375
  7. Phagocyte partnership during the onset and resolution of inflammation.
    Nat Rev Immunol. 2010 Jun;10(6):427-39 PMID: 20498669
  8. Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis.
    Science. 2009 Apr 17;324(5925):384-7 PMID: 19325080
  9. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration.
    J Exp Med. 2004 Dec 20;200(12):1571-80 PMID: 15611287
  10. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia.
    J Leukoc Biol. 2010 Jul;88(1):211-20 PMID: 20400675
  11. Chemokines: sirens of neutrophil recruitment-but is it just one song?
    Immunity. 2010 Aug 27;33(2):148-9 PMID: 20732637
  12. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  13. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury.
    Am J Physiol. 1988 Dec;255(6 Pt 2):H1269-75 PMID: 3059826
  14. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids.
    J Exp Med. 2008 Apr 14;205(4):915-27 PMID: 18362172
  15. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense.
    Nat Med. 2008 Sep;14(9):949-53 PMID: 18690244
  16. Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice.
    Am J Physiol. 1999 Jun;276(6):H1943-50 PMID: 10362674
  17. Heparin or heparan sulfate--what is the difference?
    Thromb Haemost. 1991 Jul 12;66(1):44-8 PMID: 1926051
  18. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
    Cell. 1999 Jun 25;97(7):889-901 PMID: 10399917
  19. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus.
    J Immunol. 2010 Dec 15;185(12):7413-25 PMID: 21098229
  20. CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation.
    Nat Med. 2010 Sep;16(9):1018-23 PMID: 20818377
  21. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils.
    Blood. 2010 Sep 16;116(11):1924-31 PMID: 20530797
  22. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo.
    Nat Immunol. 2011 Jun 26;12(8):761-9 PMID: 21706006
  23. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus.
    Immunity. 2004 Aug;21(2):215-26 PMID: 15308102
  24. Multistep navigation and the combinatorial control of leukocyte chemotaxis.
    J Cell Biol. 1997 Dec 1;139(5):1349-60 PMID: 9382879
  25. JAM-C regulates unidirectional monocyte transendothelial migration in inflammation.
    Blood. 2007 Oct 1;110(7):2545-55 PMID: 17625065
  26. Management of sepsis in neutropenic patients: guidelines from the infectious diseases working party of the German Society of Hematology and Oncology.
    Ann Oncol. 2011 May;22(5):1019-1029 PMID: 21041377
  27. Signalling pathways regulating human neutrophil migration induced by secretory phospholipases A2.
    Toxicon. 2004 Oct;44(5):473-81 PMID: 15450921
  28. Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies.
    Anesth Analg. 2005 Aug;101(2):488-498 PMID: 16037166
  29. Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis.
    J Immunol. 1999 Feb 15;162(4):2341-6 PMID: 9973513
  30. Platelet functions beyond hemostasis.
    J Thromb Haemost. 2009 Nov;7(11):1759-66 PMID: 19691483
  31. Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP.
    J Exp Med. 1998 Mar 16;187(6):903-15 PMID: 9500793
  32. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils.
    J Exp Med. 2006 Jun 12;203(6):1519-32 PMID: 16754715
  33. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.
    Nature. 2009 Oct 29;461(7268):1287-91 PMID: 19865173
  34. Mechanisms of leukocyte sequestration in inflamed lungs.
    Microcirculation. 2001 Apr;8(2):71-88 PMID: 11379793
  35. Sepsis: a new hypothesis for pathogenesis of the disease process.
    Chest. 1997 Jul;112(1):235-43 PMID: 9228382
  36. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.
    J Clin Invest. 1997 Jun 1;99(11):2782-90 PMID: 9169509
  37. The sterile inflammatory response.
    Annu Rev Immunol. 2010;28:321-42 PMID: 20307211
  38. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model.
    Cell Tissue Res. 2010 Feb;339(2):437-48 PMID: 20012648
  39. VE-cadherin antibody accelerates neutrophil recruitment in vivo.
    J Cell Sci. 1997 Mar;110 ( Pt 5):583-8 PMID: 9092940
  40. Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39.
    J Clin Invest. 2009 May;119(5):1136-49 PMID: 19381014
  41. Regulation of neutrophil homeostasis.
    Curr Opin Hematol. 2007 Jan;14(1):3-8 PMID: 17133093
  42. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin.
    Immunity. 2001 Mar;14(3):303-13 PMID: 11290339
  43. Neutrophil extracellular traps kill bacteria.
    Science. 2004 Mar 5;303(5663):1532-5 PMID: 15001782
  44. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils.
    Nat Immunol. 2008 Jul;9(7):743-52 PMID: 18536720
  45. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis.
    Cell. 2002 May 31;109(5):611-23 PMID: 12062104
  46. Adhesion and signaling in vascular cell-cell interactions.
    J Clin Invest. 1997 Dec 1;100(11 Suppl):S3-5 PMID: 9413392
  47. Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1.
    Nat Cell Biol. 2007 Jan;9(1):36-44 PMID: 17173042
  48. Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs.
    J Exp Med. 1996 Aug 1;184(2):639-45 PMID: 8760817
  49. Platelets and the immune continuum.
    Nat Rev Immunol. 2011 Apr;11(4):264-74 PMID: 21436837
  50. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis.
    Immunity. 2010 Aug 27;33(2):266-78 PMID: 20727790
  51. Effects of sepsis on neutrophil chemotaxis.
    Curr Opin Hematol. 2010 Jan;17(1):18-24 PMID: 19864946
  52. Heparan sulfate-protein interactions--a concept for drug design?
    Thromb Haemost. 2007 Jul;98(1):109-15 PMID: 17598000
  53. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo.
    Blood. 2011 Jan 20;117(3):942-52 PMID: 21030556
  54. Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1.
    J Clin Invest. 1999 May;103(9):1269-76 PMID: 10225970
  55. Intracellular pool of vascular endothelial growth factor in human neutrophils.
    Blood. 1997 Nov 15;90(10):4153-61 PMID: 9354686
  56. Intravascular danger signals guide neutrophils to sites of sterile inflammation.
    Science. 2010 Oct 15;330(6002):362-6 PMID: 20947763
  57. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation.
    J Cell Biol. 2009 Jan 26;184(2):205-13 PMID: 19153223
  58. Modulation of neutrophil migration by exogenous gaseous nitric oxide.
    J Leukoc Biol. 1996 Jul;60(1):94-100 PMID: 8699130
  59. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.
    Cancer Cell. 2009 Sep 8;16(3):183-94 PMID: 19732719
  60. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.
    Nat Med. 2007 Apr;13(4):463-9 PMID: 17384648
  61. Neutrophil depletion protects against murine acetaminophen hepatotoxicity.
    Hepatology. 2006 Jun;43(6):1220-30 PMID: 16729305
  62. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade.
    J Exp Med. 2006 Nov 27;203(12):2569-75 PMID: 17116736
  63. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.
    J Am Coll Cardiol. 2006 Jul 18;48(2):377-85 PMID: 16843190
  64. Platelets express functional Toll-like receptor-4.
    Blood. 2005 Oct 1;106(7):2417-23 PMID: 15961512
  65. The physiology of leukocyte recruitment: an in vivo perspective.
    J Immunol. 2008 May 15;180(10):6439-46 PMID: 18453558
  66. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection.
    Nat Med. 2010 Jun;16(6):708-12 PMID: 20473304
  67. Platelets and innate immunity.
    Cell Mol Life Sci. 2010 Feb;67(4):499-511 PMID: 20016997
  68. Sterile inflammation: sensing and reacting to damage.
    Nat Rev Immunol. 2010 Dec;10(12):826-37 PMID: 21088683
  69. Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo.
    Science. 1993 Dec 3;262(5139):1580-2 PMID: 8248808
  70. Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke.
    Stroke. 1992 Sep;23(9):1367-79 PMID: 1519296
  71. Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature.
    J Immunol. 2009 Jun 1;182(11):6870-8 PMID: 19454683
  72. Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.
    J Clin Invest. 1997 Mar 1;99(5):975-86 PMID: 9062356
  73. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2.
    J Biol Chem. 2007 Jun 22;282(25):18265-18275 PMID: 17400552
  74. Getting to the site of inflammation: the leukocyte adhesion cascade updated.
    Nat Rev Immunol. 2007 Sep;7(9):678-89 PMID: 17717539
  75. How do microbes evade neutrophil killing?
    Cell Microbiol. 2006 Nov;8(11):1687-96 PMID: 16939535
  76. Sequential chemotactic and phagocytic activation of human polymorphonuclear neutrophils.
    Infect Immun. 2007 Aug;75(8):3989-98 PMID: 17526745
  77. How dying cells alert the immune system to danger.
    Nat Rev Immunol. 2008 Apr;8(4):279-89 PMID: 18340345
  78. Acute microvascular effects of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine: comparisons with leukotriene B4.
    Microvasc Res. 1989 Jan;37(1):53-69 PMID: 2537922
  79. Interactive protrusive structures during leukocyte adhesion and transendothelial migration.
    Front Biosci. 2004 May 01;9:1849-63 PMID: 14977592
  80. Novel cell death program leads to neutrophil extracellular traps.
    J Cell Biol. 2007 Jan 15;176(2):231-41 PMID: 17210947
  81. Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners.
    J Immunol. 1997 Sep 15;159(6):2893-903 PMID: 9300713
  82. Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection.
    J Clin Invest. 2009 Jul;119(7):1921-30 PMID: 19603547
  83. Chemokine-cleaving Streptococcus pyogenes protease SpyCEP is necessary and sufficient for bacterial dissemination within soft tissues and the respiratory tract.
    Mol Microbiol. 2010 Jun;76(6):1387-97 PMID: 20158613
  84. TNF-alpha promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway.
    J Leukoc Biol. 2005 Jul;78(1):210-9 PMID: 15845648
  85. Neutrophil mobilization and clearance in the bone marrow.
    Immunology. 2008 Nov;125(3):281-8 PMID: 19128361
  86. Interleukin 8 (monocyte-derived neutrophil chemotactic factor) dynamically regulates its own receptor expression on human neutrophils.
    J Biol Chem. 1990 Jan 5;265(1):183-9 PMID: 2403554
  87. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets.
    Diabetes. 2010 Oct;59(10):2569-78 PMID: 20651296
  88. Extracellular histones are major mediators of death in sepsis.
    Nat Med. 2009 Nov;15(11):1318-21 PMID: 19855397
  89. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior.
    Science. 2007 Aug 3;317(5838):666-70 PMID: 17673663
  90. Selective down-regulation of neutrophil Mac-1 in endotoxemic hepatic microcirculation via IL-10.
    J Immunol. 2009 Dec 1;183(11):7557-68 PMID: 19917697
  91. Structural basis of integrin regulation and signaling.
    Annu Rev Immunol. 2007;25:619-47 PMID: 17201681
  92. The role of neutrophils in severe sepsis.
    Shock. 2008 Oct;30 Suppl 1:3-9 PMID: 18704017
  93. Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling.
    J Immunol. 2011 Jul 15;187(2):911-8 PMID: 21690321
  94. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients.
    J Cell Biol. 2002 Oct 14;159(1):91-102 PMID: 12370241
  95. Circulating mitochondrial DAMPs cause inflammatory responses to injury.
    Nature. 2010 Mar 4;464(7285):104-7 PMID: 20203610
  96. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.
    PLoS One. 2008 Feb 20;3(2):e1649 PMID: 18297135
  97. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them.
    J Cell Biol. 2004 Oct 25;167(2):377-88 PMID: 15504916
Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2514
Published
2011-11-07
Epub
2011-00-07
Pages
1381-90
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC7095830
Subset
IM
Grants
Canadian Institutes of Health Research · Canada
External Links
PubMed source DOI: 10.1038/nm.2514 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2