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(Journal of Leukocyte Biology. 2001;69:691-697.)
© 2001 by Society for Leukocyte Biology

Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37)

De Yang, Oleg Chertov and Joost J. Oppenheim

Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland

Correspondence: Dr. Joost J. Oppenheim, LMI, DBS, NCI-Frederick, Building 560, Room 21-89, Frederick, MD 21702-1201. E-mail: oppenhei{at}mail.ncifcrf.gov


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ABSTRACT
 
Defensins and cathelicidins are the two major families of mammalian anti-microbial proteins. They contribute to host, innate, anti-microbial defense by disrupting the integrity of the bacterial cell membrane. However, several members of the mammalian anti-microbial proteins including defensins and cathelicidins have been shown recently to have chemotactic effects on host cells. Human neutrophil {alpha}-defensins are chemotactic for resting, naïve CD45RA/CD4 T cells, CD8 T cells, and immature dendritic cells. Human ß-defensins are also chemotactic for immature dendritic cells but induce the migration of memory CD45RO/CD4 T cells. In contrast, cathelicidin/LL-37 is chemotactic for neutrophils, monocytes, and T cells but not for dendritic cells. Thus, these anti-microbial peptides have distinct, host-target cell spectra. The chemotactic activities of human ß-defensins and cathelicidin/LL-37 are mediated by human CC chemokine receptor 6 and formyl peptide receptor-like 1, respectively. The capacities of defensins and cathelicidins to mobilize various types of phagocytic leukocytes, immature dendritic cells, and lymphocytes, together with their other effects such as stimulating IL-8 production and mast cell degranulation, provide evidence for their participation in alerting, mobilizing, and amplifying innate and adaptive anti-microbial immunity of the host.

Key Words: chemotaxis • CCR6 • FPRL1 • phagocytic leukocytes • dendritic cells • keratinocytes • macrophages


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INTRODUCTION
 
Animals are under constant bombardment by microorganisms, yet individuals rarely manifest infection. This is primarily a result of the barrier function of intact epithelia lining the respiratory, gastrointestinal, and urogenital tracts and skin, which prevent the intrusion of microorganisms mechanically and by the constitutive production of anti-microbial chemicals and proteins [1 , 2 ]. Since the identification of the first anti-bacterial protein family of "thionins" during the early 1970s[3 ], over 400 anti-microbial proteins have thus far been identified in plants, insects, and animals [1 , 4 5 6 7 8 ]. The two major families of mammalian anti-microbial proteins that have been well-characterized are defensins and cathelicidins [7 8 9 10 ]. Defensins and cathelicidins have the capacity to kill and/or inactivate bacteria, fungi, and enveloped viruses in vitro [7 8 9 10 ]. They have also been demonstrated to contribute to host defense in vivo [11 12 13 ]. Thus, it has become clear that defensins and cathelicidins contribute to innate, anti-microbial, host defenses.

However, mammalian species manifest two additional types of anti-microbial defense mechanisms, namely innate and adaptive immunity [2 , 14 ]. Evidence is emerging suggesting that defensins and cathelicidins may also participate in galvanizing innate and adaptive anti-microbial immunity [15 , 16 ]. This study will summarize the evidence that defensins, cathelicidins, and perhaps other mammalian anti-microbial proteins as well, have evolved the capacity to participate in host innate and adaptive immune responses and to use host receptors to mobilize and activate various types of leukocytes.


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A SIMPLE OVERVIEW OF MAMMALIAN DEFENSINS AND CATHELICIDINS
 
Mammalian defensins consist of a family of cationic proteins that contain six highly conserved cysteine residues that form three pairs of intrachain-disulfide bonds. Based on the patterns of their intrachain-disulfide bridges, mammalian defensins are classified into three subfamilies, namely {alpha}-, ß-, and {theta}-defensins [7 , 8 , 17 ]. Currently, the {theta}-defensin subfamily has only one member that is cyclic with its six cysteine residues linking C1 to C6, C2 to C5, and C3 to C4 [17 ]. The three disulfide bonds of {alpha}-defensins are paired C1 to C6, C2 to C4, and C3 to C5 [7 , 9 , 18 ], and those of ß-defensins are C1 to C5, C2 to C4, and C3 to C6 [7 , 19 ]. More than 50 defensin family members have been identified in mammalian species. The number of defensins varies from one species to another. In humans, six {alpha}-defensins and three ß-defensins have been identified so far [7 8 9 , 20 21 22 23 24 ].

Cathelicidins consist of a family of anti-microbial proteins with a putative N-terminal signal peptide, a highly conserved cathelin (cathepsin L inhibitor)-like domain in the middle, and a less-conserved, C-terminal, anti-microbial domain [8 , 10 ]. About 20 cathelicidin members have been identified in mammals, however, only one cathelicidin has been identified in humans thus far [10 , 25 26 27 ]. Cleavage of human cathelicidin (hCAP18) liberates its C-terminal, anti-microbial domain, a peptide called LL-37, because it begins with two leucine residues and is 37 amino-acid residues in length. Thus, human cathelicidin is often referred to as LL-37 [10 , 28 ].

The classifications, origins, and effects on host cells of human {alpha}-defensins, ß-defensins, and cathelicidin/LL-37 are outlined in Table 1 . The expression of defensins and cathelicidins in tissues varies markedly among mammalian species. Human {alpha}-defensins 1, 2, 3, and 4 were isolated from neutrophils initially [20 , 21 ], so they are termed human neutrophil peptides (HNP)1, 2, 3, and 4 conventionally [7 , 8 ]. HNP1, 2, 3, and 4 are stored in the granules of neutrophils and monocytes/macrophages and can be released extracellularly [29 , 41 , 42 ]. Human {alpha}-defensins 5 and 6 (HD5 and 6) are products of intestinal Paneth cells primarily [9 , 22 , 43 ], although defensin 5 is also detected in reproductive tissues [44 ]. Human ß-defensin (HBD)1 is expressed in epithelial cells and skin keratinocytes constitutively [23 , 45 46 47 48 49 50 51 52 ]. In contrast, the expression of HBD2 and 3 by keratinocytes and epithelial cells in various tissues is induced predominantly by contact with bacteria or microbial products such as endotoxin or proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1 [24 , 46 , 48 , 51 , 53 54 55 ]. Cathelicidin/LL-37 is not only stored in neutrophil granules [26 27 28 ] but is also expressed by epithelial cells constitutively [56 ] and keratinocytes in response to inflammatory stimuli [57 , 58 ].


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  		Table 1. Classification, Origin, and Activity of Human Defensin and Cathelicidin


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THE CHEMOTACTIC ACTIVITIES OF HUMAN DEFENSINS AND CATHELICIDIN
 
Initially, defensins were discovered as the T cell chemoattractants released by IL-8-induced neutrophil degranulation. Sequential chromatography of neutrophil-derived T cell chemoattracting activities produced in response to IL-8 led to the identification of HNP1 and HNP2 as the chemotactic moieties for human peripheral blood T lymphocytes [29 , 42 ]. Investigation of subsets of human T cells demonstrated that HNP is chemotactic for CD4 and CD8 T cells [16 ]. Among CD4 T cells, only CD45RA naïve but not CD45RO memory subset can be chemoattracted by HNP [16 ]. The effect of HNP on human T cells motivated us to investigate whether HNP could exhibit in vivo immunomodulatory activities. HNP, when administered in vivo together with antigens, strikingly enhanced systemic antigen-specific immune responses in mice, demonstrating that HNP has potent immunoadjuvant activity [37 , 38 ]. This adjuvant activity of HNP led us to test their effect on dendritic cells (DC), the professional antigen-presenting cells (APC) [59 60 61 ]. We found that HNP is chemotactic for immature DC (iDC) generated from purified peripheral blood monocytes or cord blood CD34 hematopoietic progenitor cells [16 ]. The chemotactic activity of HNP for iDC is highly selective because neither monocytes nor CD34 cells could be chemoattracted [16 ]. Furthermore, when iDC were induced to mature, the resulting mature DC (mDC) can no longer migrate in response to HNP [16 ]. Human ß-defensin is also chemotactic for various types of leukocytes. HBD2 and to a lesser extent HBD1 induce the migration of human iDC and CD45RO memory T cells [15 ]. Again the chemotactic activity of HBD shows selectivity, because mDC, CD45RO naïve T cells, neutrophils, and monocytes could not be chemoattracted by HBD. Similar to HBD1 and 2, the recently identified HBD3 is also chemotactic for iDC, but unlike HBD1 and 2, HBD3 is also chemotactic for peripheral blood monocytes (unpublished results).

Recently, we investigated the human cathelicidin/LL-37 and found that LL-37 is chemotactic for human peripheral blood neutrophils, monocytes, and T lymphocytes [39 ]. The chemotactic effect of LL-37 on human neutrophils and T cells has also been documented by Agerberth et al. [40 ]. However, in contrast to defensin, LL-37 is not chemotactic for iDC or mDC [39 ]. Along similar lines, PR-39, one member of the porcine cathelicidin family, is shown to be chemotactic for porcine neutrophils [62 ]. Several other anti-microbial proteins in addition to defensins and cathelicidins are also chemotactic for various types of leukocytes. Azurocidin/hCAP37, an anti-microbial protein produced by human neutrophils, is chemotactic for human T cells [29 ], monocytes [63 , 64 ], and neutrophils [64 ]. Cathepsin G, an anti-microbial protein of the serine proteinase family stored in the granules of neutrophils, monocytes, and mast cells, is chemotactic for human neutrophils and monocytes [64 ]. Chymase, another member of the serine proteinase family that is produced primarily by mast cells and potentially has anti-microbial activity, is a potent chemoattractant for human neutrophils and monocytes [65 ]. Eosinophil-derived neurotoxin, a human eosinophil, granule-derived antiviral protein belonging to the ribonuclease family, is selectively chemotactic for iDC and mDC (unpublished results). Finally, we observed recently that histatin 5, a member of the salivary gland-derived anti-microbial histatins, can induce the migration of human monocytes (unpublished results). However, not every anti-microbial protein is chemotactic; for example, lysozyme is not chemotactic for human leukocytes (unpublished results). The chemotactic activities of various human anti-microbial proteins are summarized in Table 2 .


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  		Table 2. The Chemotactic Activities of Human Anti-Microbial Proteins


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IDENTIFICATION OF CHEMOTACTIC RECEPTORS FOR HBD AND LL-37
 
The chemotactic activities of HNP, HBD, and LL-37 share a number of characteristics. First, they induce chemotaxis of target cells at considerably lower doses than those required for their anti-microbial effects. To exert optimal anti-microbial effects in vitro, HNP, HBD, and LL-37 generally require concentrations higher than 10 µg/ml. However, HNP induce optimal target-cell migration at concentrations ranging from 10 to 100 ng/ml [16 , 29 ], and HBD attracts target cells at an optimal concentration of 100–1000 ng/ml [15 ]. Concentrations of 300–3000 ng/ml LL-37 are needed to induce chemotaxis of target cells [39 ]. Secondly, the chemotactic activities of defensins and LL-37 exhibit a bell-shaped, dose-response curve [15 , 16 , 29 , 39 ] typical of chemotactic factors [66 , 67 ]. Thirdly, their chemotactic activities are not affected [15 , 16 , 29 , 39 ] by serum at concentrations that, as demonstrated, inhibit their anti-microbial effects [7 , 68 ]. Lastly, their chemotactic activities are highly selective on target cells, suggesting a receptor-mediated mechanism.

The possibility that defensins and LL-37 use G protein-coupled, seven-transmembrane-domain receptor(s) to attract their target cells was tested because defensin- and LL-37-induced chemotaxis could be inhibited by pertussis toxin [15 , 16 , 39 ], a reagent capable of inhibiting Gi{alpha} protein-coupled, seven-transmembrane-domain receptors [66 , 67 , 69 ]. The fact that HNP and HBD induce the migration of iDC but not mDC [15 , 16 ] motivated us to focus on chemotactic receptors expressed selectively iDC (but not by mDC), such as CXCR1, CXCR2, CCR1, CCR2, CCR4, CCR5, CCR6, and formyl peptide receptor (FPR) [70 71 72 73 ]. Examination of cells transfected to express one of the above candidate receptors demonstrated that only human CCR6-transfectant cells were capable of migrating in response to HBD1 and HBD2, implicating CCR6 as a chemotactic receptor for HBD [15 ]. Additional key evidence in support of this conclusion includes: 1) HBD2-induced chemotaxis of CCR6-transfectant cells can be cross-desensitized by LARC, the previously identified ligand for CCR6 [69 , 72 ], and vice versa; 2) HBD2 can inhibit the binding of iodinated LARC to CCR6-transfectant cells competitively; and 3) HBD2-induced migration of human iDC can be inhibited dose-dependently by anti-human CCR6 antibody. Thus, CCR6 is a functional receptor that HBD uses to mediate its chemotactic effect [15 ]. HNP also seems to use a chemokine receptor to mediate its chemotactic effect, but its identity is still unknown [16 ].

LL-37 induces not only chemotaxis but also Ca+2+ flux in monocytes [39 ]. Therefore, we investigated the capacity of dozens of chemotactic factors, including all of the chemokines and chemoattractants, to determine which one was able to cross-desensitize LL-37-induced Ca2+ flux in monocytes. This identified an agonistic ligand specific for FPR-like 1 receptor (FPRL1), indicating that LL-37 uses FPRL1 as a receptor to mediate its action on monocytes [39 ]. Human peripheral blood neutrophils and T lymphocytes, cells known to express functional FPRL1 [67 , 74 ], can also migrate chemotactically in response to LL-37, providing additional evidence for this conclusion [39 ]. Furthermore, LL-37 induces the migration of cells transfected to express FPRL1 but not cells transfected to express FPR, a chemotactic receptor showing the highest homology with FPRL1. These data enabled us to conclude that FPRL1 is a functional receptor for LL-37 [39 ].


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OTHER ACTIVITIES OF HUMAN DEFENSINS AND CATHELICIDIN/LL-37
 
Anti-microbial proteins have been shown to have a variety of biological effects on the host in addition to leukocyte chemotaxis (Table 1) . HNP has been shown to cause mast cell degranulation [75 ], stimulate IL-8 production by human bronchial and lung epithelial cells [30 , 31 ], modulate complement activation [32 33 34 ], suppress glucocorticoid production [35 , 36 , 76 , 77 ], and enhance the proliferation of T cells and their production of cytokines [37 ]. The effects of neutrophil {alpha}-defensins on complement activation are mediated by binding to complement C1 [32 33 34 ], and the capacity of neutrophil {alpha}-defensins to suppress glucocorticoid production is achieved by blocking the binding of adrenocorticotropic hormone to its receptor [35 , 77 ]. However, the capacities of defensins and cathelicidins to stimulate cytokine production and cause mast-cell degranulation may also be mediated by receptor-based mechanisms.


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INCORPORATION OF DEFENSINS AND CATHELICIDINS IN ANTI-MICROBIAL IMMUNITY
 
Mammalian host defenses comprise innate and adaptive immune components [2 , 14 , 78 ]. Innate immunity represents the first line of host defense and is triggered rapidly following the detection by pattern recognition receptors of pathogen-associated molecular patterns (e.g., lipopolysaccharide, teichoic acid, peptidoglycan, mannan, and double-strand RNA) that are unique to microorganisms [2 , 78 ]. The effector branch of innate immunity consists of two major aspects. One is the release and, at times, activation of a variety of extracellular humoral mediators such as complement, cytokines, and anti-microbial proteins including defensin and cathelicidin. The other is the recruitment and activation of phagocytic granulocytes, monocytes/macrophages, and in some cases natural killer (NK) cells to sites of microbial invasion to combat the invading pathogens. Adaptive immunity is induced when T lymphocytes are activated in response to antigens presented by APC in conjunction with major histocompatibility complex (MHC) class I and class II molecules and concomitant APC-derived costimulatory signals [14 , 61 , 78 , 79 ]. The T helper cells, in turn, promote antigenic activation of B cells, which results in the production of antigen-specific antibodies that neutralize pathogen-derived toxins, block the infectivity of invading pathogens, and promote their opsonization and elimination by phagocytes. T cell activation generates CD4 and CD8 effector T cells that produce cytokines capable of activating phagocytes to eliminate pathogens more efficiently and also kill cells infected by intracellular pathogens directly. Thus, adaptive immunity, in addition to resulting in clonal expansion of T and B cells, also further activates and promotes innate host defenses.

Some of the defensins (e.g., HBD1) and cathelicidins are produced constitutively by keratinocytes and other epithelial cells and contribute to the barrier functions that provide a first line of defenses against microbial invasion of the host. Pathogens that succeed in penetrating the barrier of epithelia and skin stimulate an increase in the production and release of {alpha}-defensins, ß-defensins (in particular, ß-defensins 2 and 3), and cathelicidins by epithelial cells, skin keratinocytes, and tissue macrophages. Thus, defensins and cathelicidins generated form local chemotactic gradients as shown in Figure 1 and have a number of other effects. 1) They kill invading pathogens directly. 2) HNP is capable of stimulating IL-8 production by human airway epithelial cells by augmenting IL-8 gene transcription [30 , 31 ]. Because IL-8 is a potent neutrophil recruiter [66 , 69 ], it is conceivable that defensins and cathelicidins promote neutrophils to migrate to sites of pathogen invasion based on their chemotactic activities [29 , 39 ] or indirectly through the induction of IL-8 [30 , 31 ]. This results in a positive-feedback loop because recruited neutrophils release additional defensins and cathelicidins to amplify innate immune responses against invading pathogens. 3) They activate phagocytes to eliminate pathogens more efficiently [80 ]. 4) They degranulate mast cells leading to the release of mast-cell granule products including histamine [75 , 81 ]. Several guinea pig, human, rabbit {alpha}-defensins, HBD2, and LL-37 are able to degranulate rat peritoneal mast cells resulting in the release of mast-cell granule products including histamine [75 , 81 ]. Because mast cells modulate neutrophil influx and bacterial clearance, and histamine is known to be able to increase the permeability of small blood vessels [82 , 83 ], defensin- and cathelicidin-induced release of mast-cell granule products including histamine would help in the recruitment of more neutrophils to the inflammatory sites. 5) Finally, these mediators of innate host defense also provide the initial signals that mobilize DC and T cells and thus alert the adaptive immune responses.



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  		Figure 1. Schematic illustration of the participation of human defensins and cathelicidin/LL-37 in innate host defense and adaptive immunity against microbial invasion. Upon microbial invasion, epithelial cells/keratinocytes and tissue macrophages (M{phi}) are induced to produce ß-defensins (esp. HBD2 and 3) and cathelicidin/LL-37. Beside their several effects on innate host defense, the defensins and cathelicidin form gradients, which, in concert with other chemotactic mediators (e.g., chemokines), result in the extravasation of various types of leukocytes to the site of infection. Recruited neutrophils (PMN) release {alpha}-defensins and more cathelicidin that amplify leukocyte recruitment further. Recruitment of PMN and monocytes (Mo) enhances innate host defense, and recruited iDC and T cells promote the induction phase and effector phase, respectively, of adaptive anti-microbial immunity. Human ß-defensins use CC chemokine receptor 6 (CCR6) as a receptor, whereas the receptor for LL-37 is FPRL1. As denoted by a question mark, the receptor for HNP {alpha}-defensins has not been identified yet.

DC are the most potent APC and the only APC that have the capacity to activate naïve CD4 T cells [59 60 61 ]. However, DC have to migrate to sites of pathogen invasion for antigen uptake and processing and must mature to be able to migrate to T cell areas of secondary lymphoid organs for antigen presentation to naïve CD4 T cells [15 , 61 , 70 71 72 73 ]. Defensins contribute to the induction of adaptive, anti-microbial immune response by recruiting more iDC to the sites of pathogen invasion chemotactically [15 , 16 ]. In addition, defensins and cathelicidins can also promote DC accumulation at the inflammatory sites by degranulating mast cells [75 , 81 ]. Mast-cell degranulation releases platelet-activating factor (PAF), a potent chemoattractant for DC [84 ]. Furthermore, activated T cells also migrate to the sites of pathogen invasion to exert some of their effector functions. Defensins and cathelicidins facilitate T cell recruitment because they are both chemotactic for T cells [15 , 16 , 29 , 39 ]. Thus, anti-microbial proteins of innate host defense, in particular, defensins, also have a bridging function of activating adaptive, anti-microbial immune responses.

The capacity of defensins to induce iDC migration would suggest the possibility that defensin can act as in vivo adjuvants. Indeed, when administered together with antigens, HNP can enhance antigen-specific humoral and cellular immune responses [37 , 38 ], providing further support for the concept that anti-microbial proteins also participate in host adaptive immunity. Defensin and cathelicidin may also influence systemic anti-microbial immunity by inhibiting immunosuppressive glucocoticoids and neutralizing endotoxins. Nanomolar concentrations of {alpha}-defensins are demonstrated to inhibit the production of immunosuppressive glucocorticoids [35 , 36 , 76 , 77 ]. In the course of systemic infections, serum levels of {alpha}-defensin can reach up to 100 µg/ml [85 , 86 ], which is more than sufficient for inhibiting glucocorticoids. Cathelicidin has been shown to be capable of binding and neutralizing lipopolysaccharide [25 , 87 ], so it can ameliorate endotoxin shock [87 ]. It is reasonable to predict that defensins and cathelicidins cooperate in vivo with many other mediators of host defense, such as cytokines, chemokines, complement, acute-response proteins, other animicrobial proteins, and cellular components in generating an orchestrated defense against invading pathogens [2 , 69 , 78 , 88 ].


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SUMMARY AND PERSPECTIVE
 
Although it is reasonably well-established that mammalian anti-microbial proteins including defensins and cathelicidins play an essential role in host innate, anti-microbial immunity, their participation in host adaptive, anti-microbial immunity has just begun to unfold. We have reviewed the chemotactic activities and receptors used by human defensins and cathelicidin/LL-37 as well as their potential participation in innate and adaptive (in particular, anti-microbial) immunity. However, many questions remain to be answered and experimentally addressed. The receptor(s) HNP uses to mediate its chemotactic activity remains to identified. Are Paneth cell-derived defensins (HD5 and 6 in humans) also chemotactic? Do defensins and cathelicidins of other species also have the capacity to mobilize various types of host leukocytes? How are the chemotactic activities of anti-microbial proteins other than defensins and cathelicidins mediated? How many anti-microbial peptides remain to be identified? It is our hope that this review will stimulate more interest and attention to this particular area.


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ACKNOWLEDGEMENTS
 
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. The publisher or recipient acknowledges the right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

Received November 5, 2000; revised December 22, 2000; accepted December 28, 2000.


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