Trends in Immunology
ReviewSpecial issue: novel functions of neutrophilsAlarmins link neutrophils and dendritic cells
Introduction
Neutrophils are rapidly induced to degranulate in the inflammatory microenvironment by a wide variety of stimulants such as formyl-methionyl-leucyl-phenylalanine (fMLF), C5a, platelet-activating factor (PAF), lipopolysaccharide (LPS) and tumor necrosis factor (TNF) [1]. The granules of neutrophils sequentially release several hundred constitutively expressed proteins [2], including proinflammatory mediators with maturational effects on dendritic cells (DCs) [3]. Immature DCs present at sites of infection where activated neutrophils degranulate are thus potentially influenced by numerous granule-derived mediators. These include ‘alarmins’ that rapidly galvanize antigen-presenting cells (APCs) and activate innate and adaptive immune responses. We have termed them ‘alarmins’ because they represent the first host response to exogenous (infections) and endogenous (injuries) danger signals 4, 5. Alarmins have the dual capacities to recruit [6] and to activate inflammatory cells including DCs 4, 5 using Giα-protein-coupled receptor(s) (GiPCR) and activating receptor(s) respectively (Box 1). Alarmins rapidly marshal the host's innate inflammatory responses by activating recruited inflammatory cells to produce cytokines and to develop immature DCs into mature DCs capable of inducing antigen-specific adaptive immune responses [7]. Neutrophil-derived alarmins include a number of human antimicrobial peptides such as α-defensins 8, 9, 10, cathelicidin 11, 12 and lactoferrin 13, 14. In addition, cell injury/necrosis of neutrophils results in the release of nuclear binding proteins with alarmin activity, such as high-mobility group box-1 (HMGB1) protein 15, 16, 17. It must be pointed out that not all antimicrobial peptides or proteins released by degranulation and cell injury are alarmins. We have not been able to show that neutrophil-derived azurocidin, transferrin, lysozyme, myeloperoxidase, bactericidal/permeability-increasing protein, elastase or cathepsin G are able to chemoattract and activate APCs (Table 1). Nevertheless, some of these molecules play important alternative roles in promoting innate immunity.
Section snippets
α-Defensins
α-Defensins are small (3–4 kDa) cationic host-derived antimicrobial peptides that have been identified in humans, monkeys and several rodent species. They were primarily isolated from the azurophilic granules of human neutrophils and thus are referred to as human neutrophil peptides (HNPs) 8, 18. They are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine and are active at micromolar concentrations against many bacteria, fungi and
Cathelicidins
Cathelicidins are a family of mammalian antimicrobial proteins that consist of an N-terminal putative signal peptide, a conserved cathelin-like domain and a C-terminal antimicrobial domain that varies remarkably in size (ranging from 12 to 97 amino acids) [29]. More than 40 members of the cathelicidin family have been identified in different species; however, humans and mice each produce only one cathelicidin, called human cationic antimicrobial protein 18 (hCAP18) and the ortholog
Lactoferrin
Lactoferrin, a 703 amino acid (80 kDa) glycoprotein that belongs to the transferrin family of iron-binding proteins, was originally isolated from milk and shown to exhibit antimicrobial activity [49]. Lactoferrin has anti-bacterial, anti-viral and anti-fungal activities based on iron deprivation [49]. However, lactoferrin also has antimicrobial effects based on binding microbial LPS and glycosaminoglycans and other surface receptors 49, 50, 51. Furthermore, lactoferrin knockout mice exhibit
High-mobility group box-1 protein (HMGB1)
HMGB1, a member of the HMG superfamily, is a 215 amino acid non-histone chromosomal binding protein that is normally located in the nucleus where it regulates chromosome stability and the transcription of certain genes [74]. This vital role of HMGB1 probably accounts for the fact that gene disruption has lethal consequences [75]. HMGB1 is released extracellularly as a result of loss of membrane integrity upon necrosis of nucleated cells (including neutrophils). Mononuclear leukocytes can also
Alarmins link neutrophils to DCs
Neutrophil-derived alarmins contribute to the recruitment of DCs in several ways (Figure 1). First, certain α-defensins and HMGB1 are chemotactic for immature DCs and can contribute directly to local recruitment of DCs 9, 17. Lactoferrin and cathelicidin, however, are chemotactic for monocytes 11, 13, 26, 28, 94, thus contributing to the recruitment of potential precursors of DCs 94, 95. Furthermore, neutrophil-derived alarmins indirectly contribute to recruitment of DCs by inducing the
Conclusion
One can ask whether there is a real need to propose a new term such as ‘alarmin’? Alarmins certainly act in concert with PAMPs in response to infections, but might play a more pivotal role in response to traumatic injuries. The fact that neutrophils as well as other leukocytes and epithelial cells can rapidly release stored proteins or peptides that mobilize and activate host immune responses distinguishes these molecules from cytokines. Cytokines certainly respond to danger signals in defense
Acknowledgements
This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center
References (101)
Neutrophil granules: a library of innate immunity proteins
Trends Immunol
(2007)- et al.
Alarmins: chemotactic activators of immune responses
Curr Opin Immunol
(2005) - et al.
Discovery of alpha-defensins in basal mammals
Dev Comp Immunol
(2007) Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family
J. Biol. Chem.
(1989)- et al.
Paneth cell of the human small intestine express an antimicrobial peptide gene
J. Biol. Chem.
(1992) - et al.
Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel
FEBS Lett.
(1993) Establishment of radioimmunoassay for human neutrophil peptides and their increases in plasma and neutrophil in infection
Biochem. Biophys. Res. Commun.
(1993)The human antimicrobial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils
Blood
(1997)Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds
Blood
(2001)Chemotactic and protease-inhibiting activities of antibiotic peptide precursors
FEBS Lett.
(1993)
The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations
Blood
Stimulus-dependent impairment of the neutrophil oxidative burst response in lactoferrin-deficient mice
Am J Pathol
New immunosensor for lactoferrin determination in human milk and several pharmaceutical dairy milk products recommended for the unweaned diet
J Pharm Biomed Anal
Lactoferrin immunomodulation of DTH response in mice
Int Immunopharmacol
Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways
Cell Immunol
Lactoferrin augments BCG vaccine efficacy to generate T helper response and subsequent protection against challenge with virulent Mycobacterium tuberculosis
Int Immunopharmacol
Immunochemical detection of human lactoferrin in feces as a new marker for inflammatory gastrointestinal disorders and colon cancer
Clin Biochem
Revised nomenclature for high mobility group (HMG) chromosomal proteins
Trends Biochem Sci
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA
Blood
NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1
Blood
The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system
J Biol Chem
Neutrophil secretion products pave the way for inflammatory monocytes
Blood
Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo
Immunity
Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense
Annu. Rev. Immunol.
Antimicrobial proteins act as “alarmins” in joint immune defense
Arthritis Rheum.
β-Defensins: Linking innate and adaptive immunity through dendritic and T cell CCR6
Science
Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2
Science
Defensins: Natural peptide antibiotics of human neutrophils
J. Clin. Invest.
Human neutrophil defensins selectively chemoattract naïve T and immature dendritic cells
J. Leukoc. Biol.
Mechanisms for induction of acquired host immunity by neutrophil peptide defensins
Proc. Natl. Acad. Sci. USA
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
J. Exp. Med.
Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant
J Immunol
Lactoferrin acts as an alarmin to promote the recruitment and activation of APCs and antigen-specific immune responses
J Immunol
Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells
Faseb J
HMGB1 is an endogenous immune adjuvant released by necrotic cells
EMBO Rep.
High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization
J. Immunol.
High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin
J Leukoc Biol
Primary structures of three human neutrophil defensins
J. Clin. Invest.
Immunomodulatory properties of defensins and cathelicidins
Curr Top Microbiol Immunol
Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens
Int. Immunol.
Monocyte-chemotactic activity of defensins from human neutrophils
J. Clin. Invest.
Alpha-defensin 1 (human neutrophil protein 1) as an antichemotactic agent for human polymorphonuclear leukocytes
Antimicrob Agents Chemother
Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human alpha-defensin family
J Immunol
Cathelicidins, essential gene-encoded mammalian antibiotics
J Mol Med
Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense
J. Immunol.
Chemoattractant properties of PR-39, a neutrophil antibacterial peptide
J. Leukoc. Biol.
A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis
Immunology
The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization
J. Immunol.
Antimicrobial peptide LL-37 internalized by immature human dendritic cells alters their phenotype
Scand J Immunol
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