Neutrophils and keratinocytes in innate immunity—cooperative actions to provide antimicrobial defense at the right time and place

The human neutrophil is a professional phagocyte of fundamental importance for defense against microorganisms, as witnessed by the life‐threatening infections occurring in patients with neutropenia or with defects that result in decreased microbicidal activity of the neutrophil [ 1 , 2 ]. Likewise, the skin and mucosal surfaces provide important barriers against infections. Traditionally, these major defense systems, the epithelial cells and the neutrophils, have been viewed as limited in their armory: The epithelial cells provide defense by constituting a physical barrier, and the neutrophils provide instant delivery of preformed antimicrobial substances or on‐the‐spot assembly of the multicomponent reduced nicotinamide adenine dinucleotide phosphate oxidase from stored components for the generation of reactive oxygen metabolites. Recent research has shown that epithelial cells are highly dynamic and able to generate antimicrobial peptides in response not only to microbial infection itself [ 3 4 5 6 ] but more importantly, to the growth factors that are called into play when the physical barrier is broken, and the risk of microbial infection is imminent [ 7 ]. Likewise, the neutrophil changes its profile of actively transcribed genes when it diapedeses into wounded skin [ 8 ]. This results in generation of signaling molecules, some of which support the growth and antimicrobial potential of keratinocytes and epithelial cells. This paper will highlight some recent advances in this field.

[1]  J. Malm,et al.  Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin. A NOVEL MECHANISM OF GENERATING ANTIMICROBIAL PEPTIDES IN VAGINA. VOLUME 278 (2003) PAGES 28540-28546 , 2006, Journal of Biological Chemistry.

[2]  J. Calafat,et al.  Localization of serglycin in human neutrophil granulocytes and their precursors , 2004, Journal of leukocyte biology.

[3]  S. Knudsen,et al.  The Transcriptional Activation Program of Human Neutrophils in Skin Lesions Supports Their Important Role in Wound Healing1 , 2004, The Journal of Immunology.

[4]  Scott I. Simon,et al.  Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils1 , 2004, The Journal of Immunology.

[5]  A. Weyrich,et al.  Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. Eklund,et al.  The Human Antimicrobial Peptide LL-37 Transfers Extracellular DNA Plasmid to the Nuclear Compartment of Mammalian Cells via Lipid Rafts and Proteoglycan-dependent Endocytosis* , 2004, Journal of Biological Chemistry.

[7]  M. Duchen,et al.  The large-conductance Ca2+-activated K+ channel is essential for innate immunity , 2004, Nature.

[8]  M. Zanetti Cathelicidins, multifunctional peptides of the innate immunity , 2004, Journal of leukocyte biology.

[9]  M. Sehested,et al.  Neutrophil Gelatinase-Associated Lipocalin Is Up-Regulated in Human Epithelial Cells by IL-1β, but Not by TNF-α 1 , 2003, The Journal of Immunology.

[10]  K. Rabe,et al.  The Antimicrobial Peptide LL-37 Activates Innate Immunity at the Airway Epithelial Surface by Transactivation of the Epidermal Growth Factor Receptor 1 , 2003, The Journal of Immunology.

[11]  M. Fink,et al.  Protective efficacy of CAP18106-138-immunoglobulin G in sepsis. , 2003, The Journal of infectious diseases.

[12]  J. Malm,et al.  Processing of Seminal Plasma hCAP-18 to ALL-38 by Gastricsin , 2003, Journal of Biological Chemistry.

[13]  O. Levy,et al.  Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia. , 2003, Biochemical Society transactions.

[14]  T. Ganz,et al.  Wound Healing and Expression of Antimicrobial Peptides/Polypeptides in Human Keratinocytes, a Consequence of Common Growth Factors1 , 2003, The Journal of Immunology.

[15]  S. Zahler,et al.  An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. , 2003, The Journal of clinical investigation.

[16]  J. Cowland,et al.  The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow. , 2003, Blood.

[17]  V. Nizet,et al.  Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. , 2003, The Journal of investigative dermatology.

[18]  A. Weyrich,et al.  Cell-cell interactions: leukocyte-endothelial interactions. , 2003, Current opinion in hematology.

[19]  M. Ståhle-Bäckdahl,et al.  The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. , 2003, The Journal of investigative dermatology.

[20]  L. Boxer Neutrophil abnormalities. , 2003, Pediatrics in review.

[21]  D. Ribatti,et al.  Analysis of the role of chemokines in angiogenesis. , 2003, Journal of immunological methods.

[22]  P. Carmeliet,et al.  uPAR: a versatile signalling orchestrator , 2002, Nature Reviews Molecular Cell Biology.

[23]  R. Meech,et al.  Proton Conduction through gp91phox , 2002, The Journal of general physiology.

[24]  K. P. O'Brien,et al.  Neutrophil gelatinase‐associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin , 2002, Experimental dermatology.

[25]  R. Strong,et al.  The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. , 2002, Molecular cell.

[26]  R. Hancock,et al.  The Human Antimicrobial Peptide LL-37 Is a Multifunctional Modulator of Innate Immune Responses1 , 2002, The Journal of Immunology.

[27]  A. Johnsen,et al.  Defensin-rich granules of human neutrophils: characterization of secretory properties. , 2002, Biochimica et biophysica acta.

[28]  S. Grinstein,et al.  Expression and subcellular localization of NRAMP1 in human neutrophil granules. , 2002, Blood.

[29]  Giorgio Gabella,et al.  Killing activity of neutrophils is mediated through activation of proteases by K+ flux , 2002, Nature.

[30]  S. Grinstein,et al.  Determinants of the Phagosomal pH in Neutrophils* , 2002, The Journal of Biological Chemistry.

[31]  H Phillip Koeffler,et al.  Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBPϵ , 2002, Current opinion in hematology.

[32]  T. Ganz,et al.  Cathelicidins: a family of endogenous antimicrobial peptides , 2002, Current opinion in hematology.

[33]  Takaaki Ohtake,et al.  Innate antimicrobial peptide protects the skin from invasive bacterial infection , 2001, Nature.

[34]  I. Nagaoka,et al.  Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells1 , 2001, The Journal of Immunology.

[35]  V. Nizet,et al.  Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. , 2001, The Journal of investigative dermatology.

[36]  J. Calafat,et al.  Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. , 2001, Blood.

[37]  C. Overall,et al.  Subcellular Distribution and Cytokine- and Chemokine-regulated Secretion of Leukolysin/MT6-MMP/MMP-25 in Neutrophils* , 2001, The Journal of Biological Chemistry.

[38]  P. Khavari,et al.  In vivo restoration of laminin 5 β3 expression and function in junctional epidermolysis bullosa , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M. Goebeler,et al.  Chemokines in cutaneous wound healing , 2001, Journal of leukocyte biology.

[40]  J. Schröder,et al.  Isolation and Characterization of Human β-Defensin-3, a Novel Human Inducible Peptide Antibiotic* , 2001, The Journal of Biological Chemistry.

[41]  Ji Ming Wang,et al.  Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells , 2000, The Journal of experimental medicine.

[42]  H. Lilja,et al.  The Human Cationic Antimicrobial Protein (hCAP-18) Is Expressed in the Epithelium of Human Epididymis, Is Present in Seminal Plasma at High Concentrations, and Is Attached to Spermatozoa , 2000, Infection and Immunity.

[43]  P. Follin,et al.  Skin chamber technique for study of in vivo exudated human neutrophils. , 1999, Journal of immunological methods.

[44]  M. Kagnoff,et al.  Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. , 1999, Journal of immunology.

[45]  E. Greenberg,et al.  Production of β-defensins by human airway epithelia , 1998 .

[46]  N. Borregaard,et al.  Timing, targeting and sorting of azurophil granule proteins in human myeloid cells , 1998, Leukemia.

[47]  K. Weinberg,et al.  A Novel, Myeloid Transcription Factor, C/EBPε, Is Upregulated During Granulocytic, But Not Monocytic, Differentiation , 1997 .

[48]  D. Bainton,et al.  The Human Antibacterial Cathelicidin, hCAP-18, Is Synthesized in Myelocytes and Metamyelocytes and Localized to Specific Granules in Neutrophils , 1997 .

[49]  G. Banting,et al.  The arachidonate-activatable, NADPH oxidase-associated H+ channel is contained within the multi-membrane-spanning N-terminal region of gp91-phox. , 1997, The Biochemical journal.

[50]  M. Kagnoff,et al.  Epithelial cells as sensors for microbial infection. , 1997, The Journal of clinical investigation.

[51]  D R Flower,et al.  The lipocalin protein family: structure and function. , 1996, The Biochemical journal.

[52]  J. Calafat,et al.  Targeting of proteins to granule subsets is determined by timing and not by sorting: The specific granule protein NGAL is localized to azurophil granules when expressed in HL-60 cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Odeberg,et al.  The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. , 1996, European journal of biochemistry.

[54]  B. Nielsen,et al.  Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. , 1996, Gut.

[55]  J. Neilands Siderophores: Structure and Function of Microbial Iron Transport Compounds (*) , 1995, The Journal of Biological Chemistry.

[56]  J. Odeberg,et al.  FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[57]  U. Gullberg,et al.  The heterogeneity of azurophil granules in neutrophil promyelocytes: immunogold localization of myeloperoxidase, cathepsin G, elastase, proteinase 3, and bactericidal/permeability increasing protein. , 1994, Blood.

[58]  Paul Kubes,et al.  The microcirculation and inflammation: modulation of leukocyte‐endothelial cell adhesion , 1994, Journal of leukocyte biology.

[59]  D. Adams,et al.  Leucocyte-endothelial interactions and regulation of leucocyte migration , 1994, The Lancet.

[60]  H. Sengeløv,et al.  Isolation and characterization of gelatinase granules from human neutrophils. , 1994, Blood.

[61]  H. Sengeløv,et al.  Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. , 1994, Blood.

[62]  H. Sengeløv,et al.  Structural and functional heterogeneity among peroxidase-negative granules in human neutrophils: identification of a distinct gelatinase-containing granule subset by combined immunocytochemistry and subcellular fractionation. , 1993, Blood.

[63]  H. Sengeløv,et al.  Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. , 1993, The Journal of biological chemistry.

[64]  John I. Gallin,et al.  Inflammation: Basic Principles and Clinical Correlates , 1992 .

[65]  A. Gottlieb,et al.  The insulin-like growth factor I receptor is overexpressed in psoriatic epidermis, but is differentially regulated from the epidermal growth factor receptor , 1992, The Journal of experimental medicine.

[66]  J. D. Benson,et al.  Insulin-like growth factors I and II expression in the healing wound. , 1992, The Journal of surgical research.

[67]  R. Parmley,et al.  Defensin-rich dense granules of human neutrophils. , 1987, Blood.

[68]  I. Olsson,et al.  Cellular and subcellular localization of the bactericidal/permeability-increasing protein of neutrophils. , 1987, Blood.

[69]  T. Ganz DEFENSINS: NATURAL PEPTIDE ANTIBIOTICS IN HUMAN NEUTROPHILS , 1986 .

[70]  R I Lehrer,et al.  Primary structures of three human neutrophil defensins. , 1985, The Journal of clinical investigation.

[71]  U. Testa,et al.  Ultrastructural localization of lactoferrin and myeloperoxidase in human neutrophils by immunogold. , 1985, Blood.

[72]  A. Tauber,et al.  Proton secretion by stimulated neutrophils. Significance of hexose monophosphate shunt activity as source of electrons and protons for the respiratory burst. , 1984, The Journal of clinical investigation.

[73]  M. Geisow,et al.  The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH , 1981, Nature.

[74]  T. Kuijpers Clinical symptoms and neutropenia: the balance of neutrophil development, functional activity, and cell death , 2007, European Journal of Pediatrics.

[75]  T. Ganz,et al.  Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. , 2001, Blood.

[76]  D. Bainton,et al.  The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. , 1997, Blood.

[77]  P. Ehrlich Granules of the Human Neutrophilic Polymorphonuclear Leukocyte , 1997 .