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(Journal of Leukocyte Biology. 2005;77:439-443.)
© 2005 by Society for Leukocyte Biology

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

Niels Borregaard*,1, Kim Theilgaard-Mönch*, Jack B. Cowland*, Mona Ståhle{dagger} and Ole E. Sørensen*

* The Granulocyte Research Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark; and
{dagger} Department of Dermatology, Karolinska Institutet, Stockholm, Sweden

1Correspondence: The Granulocyte Research Laboratory, Department of Hematology, Rigshospitalet-4042, 9 Blegdamsvej, DK-2100, University of Copenhagen, Copenhagen, Denmark. E-mail: borregaard{at}rh.dk


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ABSTRACT
 
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.

Key Words: hCAP-18 • NGAL • antibiotic peptides


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REGULATION OF NEUTROPHIL GRANULE PROTEIN EXPRESSION
 
Neutrophil antimicrobial peptides are synthesized during myelopoiesis and stored in distinct cytoplasmic granules, which are released extracellularly and/or to the phagocytic vacuole [9 ]. The granular localization of the antimicrobial peptides depends on the stage of neutrophil maturation at which the peptides are synthesized [10 ]. Most neutrophil antimicrobial peptides are induced by the myeloid-specific transcription factor C/EBP{varepsilon}, the concentration that peaks at the myelocyte metamyelocyte stage [11 12 13 ]. Consequently, the majority of antibiotic peptides localizes to secondary granules, also known as specific granules. Although this pertains without restriction to the neutrophil gelatinase-associated lipocalin (NGAL) [14 ] and the cathelicidin human cationic antimicrobial protein 18 (hCAP-18) [15 ], the {alpha}-defensins (human neutrophil peptides 1–4) [16 ], although still dependent on C/EBP{varepsilon} [12 ], are only sorted to granules at the promyelocyte stage, and amply present in a late-appearing subset of azurophil (or primary) granules, where they constitute ~50% of the total mass of protein [17 18 19 ]. Still, like NGAL and hCAP-18, the majority of {alpha}-defensins is synthesized by myelocytes but in contrast to NGAL and hCAP-18, is not sorted to granules at this stage of cellular maturation and is consequently released to the bone marrow plasma as unprocessed propeptides [20 ]. Bactericidal permeability-increasing protein, another major antimicrobial protein of neutrophils exclusively present in azurophil granules [21 , 22 ], is also dependent on C/EBP{varepsilon} [12 ] and known to be expressed in epithelial cells [23 ].

Once the neutrophil has terminated its production of the above-mentioned antimicrobial peptides by exit from the metamyelocyte stage, this production is not reactivated at any later stage, not even when neutrophils migrate into tissues, as recently shown in a global microarray analysis where the mRNA profile of skin-window neutrophils was compared with that of blood neutrophils [8 ]. Thus, the antimicrobial peptides are synthesized and stored in granules during maturation of neutrophils in the bone marrow—a process that is completed in ~2 weeks [24 ].


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ANTIMICROBIAL PEPTIDES COMMON TO KERATINOCYTES AND NEUTROPHILS
 
hCAP-18, the only human member of the cathelicidin family of antimicrobial peptides [25 ], is a major constituent of specific granules of the human neutrophil [15 ]. Although initially thought to be just a proantibiotic protein like other cathelicidins with functions only attributable to the antimicrobial activity of the C-terminal sequence encoded by the fourth exon [25 26 27 ], recent data have shown that the cathelin part exerts independent functions in host defense by acting as a protease inhibitor with activity against lysosomal proteases [28 ] and furthermore, that the C-terminal peptide (termed LL-37 when it consists of the C-terminal 37 amino acids of hCAP18) is not only antimicrobial but is also a chemoattractant that attracts other neutrophils, monocytes, and T lymphocytes via the formyl peptide receptor-like 1 (FPRL1) [29 ] and is capable of generating intracellular signals also in epithelial cells [30 , 31 ]. LL-37 has also been shown to stimulate angiogenesis [32 ]. Most recently, it was demonstrated that LL-37 may protect plasmid DNA and mediate its cellular uptake and subsequent eukaryotic expression [33 ]. Whether this is only a laboratory phenomenon that may be used in facilitation of transfection or may lead to cellular uptake of bacterial genes at sites of microbial infection and potentially to autoimmune phenomena remains to be shown. In addition, the intact propeptide and the C-terminal peptide can bind endotoxin [34 ] and provide protection against endotoxin-mediated damage [35 ]. Thus, for many reasons, hCAP-18 cannot be viewed solely as a proantimicrobial protein, which works largely in the phagocytic vacuole along with other antimicrobial agents present there. This conclusion was also reached when proteolytic activation of hCAP-18 was investigated in phagocytosing neutrophils [36 ]. First, neutrophils from skin windows are much more apt phagocytes than neutrophils from circulating blood [36 ]. This probably reflects the fact that neutrophils generally work in tissues not in blood. Second, although hCAP-18 was delivered to the phagocytic vacuole and was exposed to the three major proteases from azurophil granules, elastase, cathepsin G, and proteinase 3 (PR3), hCAP-18 was not proteolytically processed inside the phagocytic vacuole [36 ]. This lack of processing is most likely a result of the acidic milieu of the phagocytic vacuole. However, once hCAP-18 was released from cells, it was readily processed to generate the C-terminal antimicrobial peptide known as LL-37 and cathelin [36 ]. Contrary to other species where processing of cathelicidins is carried out by elastase [27 ], the specific cleavage of the human cathelicidin, hCAP-18, released from neutrophils, is mediated by PR3, which is active at neutral pH [36 ]. We are aware of a persistently advanced claim that the phagocytic vacuole of human neutrophils is alkaline as a result of a postulated proton-consuming activity of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [37 , 38 ], which should result further in influx of K+ into the phagocytic vacuole, releasing the neutral proteases from a postulated tight-binding to the proteoglycan, serglycin, supposed to be present in the granule matrix [37 , 39 ]. Several observations argue against this. First, serglycin is not present in phagocytic vacuoles of human neutrophils [40 ]. Second, the activity of the NADPH oxidase is neutral, and protons are transported along with electrons to secure this [41 42 43 ]. The net activity of the NADPH oxidase is acidification as a result of carbonic acid generated by the hexose monophosphate shunt, which is activated by NADPH oxidase activity [41 ]. Finally, protons are pumped actively into the phagocytic vacuole by the vacuolar-type ATPase recruited to the phagocytic vacuole [44 ]. The activity of the NADPH oxidase may result in damage to the phagocytic vacuole and passive flow of H+ back into the cytosol [44 ]. However, regardless of the pH in the phagocytic vacuole, hCAP-18 is clearly not processed by neutral proteases inside the phagocytic vacuole of neutrophils [36 ]. Although it may, at first glance, seem inappropriate that intact hCAP-18 and its processing protease are liberated extracellularly from exudated neutrophils, this allows both proteins to exert extracellular functions, such as activation of epithelial cells and recruitment of other inflammatory cells, as alluded to above, and provides a protease for processing hCAP-18 generated by epithelial cells, as discussed below.

In addition to being constitutively expressed in neutrophil precursors, hCAP-18 is constitutively expressed in epithelial cells in the epididymis and is found in a high concentration in seminal fluid [45 , 46 ]. Processing occurs here by a decline of pH from the slightly alkaline pH of seminal plasma to a pH of 4 present in the vagina. The protease responsible for processing hCAP-18 in semen is the prostate-specific aspartic protease, gastricsin [47 ], which processes hCAP-18 1 amino acid N-terminal compared with processing by PR3. The resultant peptide, ALL-38, has the same antimicrobial activity as LL-37 [47 ].

hCAP-18 is induced in keratinocytes during wound healing [48 ]. This has been further investigated in human skin obtained from reconstructive surgery and experimentally wounded in culture [49 ]. Here, hCAP-18 is highly induced in keratinocytes, particularly at the migrating front. More important and unexpected, antibody to hCAP-18 completely inhibited re-epithelialization. This was in a setting without the possibility for recruitment of neutrophils or monocytes. This thus points to a double role of hCAP-18 during wound healing by providing antimicrobial defense (as evidenced by the mouse cathelicidin knockout (KO) [50 ] and the reduced bacterial clearance when extracellular processing of porcine cathelicidin has been impaired [51 ]) and by acting as an important autocrine growth factor for keratinocytes (in addition to the contribution by infiltrating neutrophils when appropriate). The latter is further supported by the impaired wound healing in the mouse KO model with experimental group A streptococcal infection [50 ] and with the inability of keratinocytes in chronic leg ulcers to express hCAP-18 [49 ]. Factors capable of inducing hCAP-18 production in keratinocytes were identified in an experimental model [7 ]. Insulin-like growth factor 1 (IGF-1) induces synthesis of hCAP-18 by keratinocytes [7 ]. The expression of IGF-1 is induced in wounds [52 ]. The receptor for IGF-1 is furthermore overexpressed in psoriatic epidermis [53 ].


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NGAL
 
NGAL is, as its name implies, a lipocalin [54 ]. Most lipocalins are transport molecules that bind and transport small lipophilic substances in their canonical lipocalin pocket [55 ]. The ligand of NGAL was recently identified as bacterial siderophores, substances that are generated by microorganisms when lack of iron is limiting their growth [56 ]. Siderophores are the strongest iron chelators known and are able to extract iron from most other organic complexes, in particular, from other iron-binding proteins such as lactoferrin and transferrin [57 ]. NGAL binds a variety of bacterial siderophores with high avidity and prevents growth of microorganisms by depriving them of iron [56 ].

NGAL, like hCAP-18, is a prominent protein of specific granules of human neutrophils [14 ]. It was named NGAL, as it was first identified as a protein complexed to the neutrophil matrix metalloproteinase (MMP), gelatinase B, or MMP-9 [54 ]. The major part of NGAL is, however, present as a homodimer or monomer in specific granules, and the major part of gelatinase is present in the distinct and highly mobilizable granule subset, gelatinase granules or tertiary granules [54 , 58 ]. Perhaps more important than its localization in specific granules is the observation that NGAL is induced in a variety of epithelial cells during inflammation. This pertains to epithelial cells of the colon [59 ] and of the respiratory tract, where the constitutive expression of NGAL in type II pneumocytes can become highly up-regulated in response to inflammation and its synthesis induced in goblet cells and ciliated cells of the bronchia at the same time [60 ]. NGAL is also induced in keratinocytes during inflammation and in skin disorders such as psoriasis [61 ]. The regulation of NGAL transcription has been studied in the type II pneumocyte cell line A549 cells. It is known that induction of NGAL transcription is critically dependent on a nuclear factor (NF)-{kappa}B site in the NGAL promoter, but an additional signal delivered by interleukin (IL)-1ß and not by tumor necrosis factor {alpha} (TNF-{alpha}) is necessary for induction of transcription and synthesis of NGAL [60 ].

In keratinocytes, IL-1ß and IGF-1, together with ligands of the epidermal growth factor receptor (EGFR), induce NGAL transcription and synthesis [7 ].

NGAL is the hitherto-only known eukaryotic protein that binds siderophores. Its localization to the phagocytic vacuole of neutrophils adds to other proteins aiming at reducing the availability of iron for microbial use, such as lactoferrin [62 ] and the iron transporter natural resistance-associated macrophage protein 1 [63 ], but its extraordinary high expression in epithelial cells during inflammation most likely also reflects its importance in host defense. It is, so far, not known whether epithelial cells themselves express receptors for NGAL, which would protect against a potential release of the siderophore from NGAL by bacterial proteases, although such may not be necessary, as NGAL is known as a highly protease-resistant molecule itself [14 ].


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NEUTROPHILS IN WOUND HEALING
 
Neutrophils circulate in blood as quiescent cells that are recruited to sites of inflammation, primarily by local changes in the endothelial cells, which activate the neutrophils to become adherent to the endothelium and migrate out into tissues to engulf and kill microorganisms, typically at sites where the skin or mucosal barriers have been broken [64 65 66 ]. We recently investigated the global changes in mRNA profiles of neutrophils during this transit from blood to skin wounds in an experimental human model in which skin windows are created by unroofing suction blisters [8 , 67 ]. Differently expressed genes (314) were identified. Notably, genes for signaling molecules, which may recruit and stimulate other inflammatory cells, were up-regulated: macrophage-inflammatory protein-1{alpha}, IL-8, growth-related oncogene-ß (GRO-ß), vascular endothelial growth factor (VEGF), IL-1ß, TNF-{alpha}, (GRO-{gamma}), and monocyte chemotactic peptide-1 (MCP-1) [68 ]. Other up-regulated chemokines/cytokines promote angiogenesis: VEGF, IL-8, GRO-{gamma}, and MCP-1 [69 ], proliferation of keratinocytes and fibroblasts (IL-8, IL-1ß, and MCP-1) [68 ], and the induction of antimicrobial gene expression in keratinocytes (IL-1ß and TNF-{alpha}) [7 ]. Additional, up-regulated genes, potentially involved in wound healing were laminin 5 ß3 [70 ], which promotes adhesion of keratinocytes to the dermal layer, and urokinase plasminogen activator, which stimulates proliferation, migration, and adhesion of keratinocytes, fibroblasts, and endothelial cells in skin wounds [71 ]. It should also be noted that a rapamycin-sensitive mechanism for transcriptional control of mRNA in activated neutrophils has recently been demonstrated, which results in generation of IL-6 receptor {alpha} chain (IL-6R{alpha}), which may play a role in recruiting additional inflammatory cells to the site of injury [72 ].


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A SYNERGISTIC MODEL
 
Hiemstra and co-workers [30 ] recently presented a key to an important synergistic effect, in which epithelial cells and neutrophils cooperate to provide wound healing and antimicrobial defense. They showed that LL-37 induced bronchial epithelial cells to activate a (supposedly) membrane-bound MMP, which would release membrane-bound proligands for the EGFR and would then be activated in this autocrine loop with resultant intracellular signaling though the mitogen-activated protein kinase pathway to ensure gene activation.

We would like to widen this model by suggesting that this may be extended to keratinocytes also (Fig. 1 ). Infiltrating neutrophils may provide intact and processed hCAP-18 to stimulate epithelial cells (including keratinocytes) and angiogenesis. In addition, neutrophils may provide MMP-9 and MMP-25 [74 , 75 ] to release EGFR ligands from epithelial cells and thus provide EGFR activation and intracellular signaling, which results in transcription of genes for antimicrobial peptides (NGAL, secretory leukocyte protease inhibitor, ß-defensin-3) and in genes for chemoattractants such as IL-8. Neutrophils may themselves secrete stimuli that activate keratinocytes, such as IL-8, MCP-1, and IL-1ß, and factors that promote angiogenesis, such as VEGF and GRO-{gamma} [8 ], and may deliver the protease PR3, which cleaves hCAP-18 generated by keratinocytes, all in all, resulting in wound healing and resistance to microbial infection.



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  		Figure 1. Diagram of neutrophils and keratinocytes during wound healing. (A) A drawing of neutrophil diapedesis into a skin wound. The neutrophils are captured by endothelial cells, locally actived at the site of injury and/or infection. This process involves endothelial selectin (E- and P-selectin)-mediated neutrophil rolling, activation, and arrest and integrin-mediated, firm adhesion and subsequent diapedesis [73 ]. (B) The pathways by which neutrophils enhance the antimicrobial potential of keratinocytes. Solid lines indicate potential action pathways. Stipulated lines indicate lines of transport. EGFR on keratinocytes may be activated directly by products from neutrophils or indirectly from EGFR ligands cleaved off by MMP liberated from neutrophils (MMP-9 and MMP-25) or from endogenous MMP activated by signals emanating from G-protein-coupled receptors (FPRL1) in response to LL-37 generated from neutrophils or from keratinocytes. The activated EGFR transmits signals resulting in activation of genes for NGAL and human ß-defensin 3 (HBD-3). IL-1ß from neutrophil may also activate keratinocyte IL-1R, which may transmit signals that result in activation of genes for NGAL and HBD-2 via NF-{kappa}B. EGF-L, EGF-like repeats.

Received July 1, 2004; revised October 4, 2004; accepted October 5, 2004.


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