MINIREVIEW Multifunctional host defense peptides: Antimicrobial peptides, the small yet big players in innate and adaptive immunity Constance Auvynet 1,2, * and Yvonne Rosenstein 1 1 Instituto de Biotecnologia, Universidad Nacional Auto ´ noma de Me ´ xico, Cuernavaca, Mor. Mexico 2 FRE 2852, Peptidome de la peau des amphibiens, CNRS ⁄ Universite ´ Pierre et Marie Curie, Paris, France Introduction Antimicrobial peptides constitute a heterogeneous group of peptides with respect to their primary and secondary structures, their antimicrobial potentials, their effects on host cells, and the regulation of their expression. Most antimicrobial peptides are small (12– 50 amino acids), have a positive charge provided by Arg and Lys residues, and an amphipathic structure that enables them to interact with bacterial membranes. Cationic peptides are divided into several subfamilies, of which the most extensively studied are the mammalian gene families of antimicrobial peptides, the cathelicidins and defensins [1–3]. A comprehensive view of the field can be obtained through recent reviews that have covered this subject extensively [4–7]. Keywords antimicrobial peptides; cathelicidins; defensins; gene expression; immunity Correspondence Y. Rosenstein, Instituto de Biotecnologia, Universidad Nacional Auto ´ noma de Me ´ xico, Av. Universidad 2001, Col. Chamilpa, Cuernavaca, Mor. 62210, Mexico Fax: +52 777 317 2388 Tel: +52 777 329 1606 E-mail: yvonne@ibt.unam.mx *Present address INSERM UMR-S 945 Immunite ´ et Infection ⁄ Universite ´ Pierre et Marie Curie, Paris, France (Received 31 May 2009, revised 3 September 2009, accepted 4 September 2009) doi:10.1111/j.1742-4658.2009.07360.x The term ‘antimicrobial peptides’ refers to a large number of peptides first characterized on the basis of their antibiotic and antifungal activities. In addition to their role as endogenous antibiotics, antimicrobial peptides, also called host defense peptides, participate in multiple aspects of immunity (inflammation, wound repair, and regulation of the adaptive immune sys- tem) as well as in maintaining homeostasis. The possibility of utilizing these multifunctional molecules to effectively combat the ever-growing group of antibiotic-resistant pathogens has intensified research aimed at improving their antibiotic activity and therapeutic potential, without the burden of an exacerbated inflammatory response, but conserving their immunomodula- tory potential. In this minireview, we focus on the contribution of small cationic antimicrobial peptides – particularly human cathelicidins and defen- sins – to the immune response and disease, highlighting recent advances in our understanding of the roles of these multifunctional molecules. Abbreviations CRAMP, murine cathelin-related antimicrobial peptide; EGFR, epidermal growth factor receptor; ET, extracellular trap; GM-CSF, granulocyte– macrophage colony-stimulating factor; HD, human defensin; hBD, human b-defensin; HNP, human neutrophil peptide (a-defensins); IFN-c, interferon-c; IL, interleukin; LPS, lipopolysaccharide; NFjB, nuclear factor kappaB; NK, natural killer; SCCE, stratum corneum chymotryptic enzyme; SCTE, stratum corneum tryptic enzyme; TCF-4, transcription factor-4; TLR, Toll-like receptor; TNF-a, tumor necrosis factor-a; VDR, vitamin D receptor. FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6497 Herein, we have centered our attention on the most recent findings regarding the transcriptional regulation of cathelicidins and defensins, and the mechanisms through which they modulate different facets of immu- nity and disease. Defensins are cationic peptides containing six Cys residues forming three intramolecular disulfide bonds. On the basis of the position of the six conserved Cys residues and on sequence identity, members of this family of peptides have been classified into a-defensins, b-defensins, and h-defensins. Defensins are widely expressed [8], and in mammalian species more than 100 have been identified. Depending on the cell, they will exert their function either in the intracellular or extracellular compartment. They exhibit bactericidal, fungicidal and antiviral activity [9–11]. Defensins are either stored in granules of neutrophils or Paneth cells or secreted by monocytes, macrophages, mast cells, natural killer (NK) cells, keratinocytes, and epithelial cells. When released into the extracellular milieu, they exert their antimicrobial activity directly by attacking the microbe membrane, and in the intracellular com- partment, they contribute to the oxygen-independent killing of phagocytosed microorganisms. Furthermore, defensins are mediators in the crosstalk between the innate and adaptive immune systems [4]. In addition to a highly conserved cathelin domain, cathelicidins have an N-terminal signal peptide and a structurally variable antimicrobial peptide at the C-ter- minus. Humans and mice have only one cathelicidin gene, whereas other mammals, such as pigs and cattle, have several genes [12]. In humans, the cathelicidin antimicrobial peptide gene encodes an inactive precur- sor protein (hCAP18) that is processed to release a 37 amino acid peptide (LL-37) from the C-terminus of the precursor protein. Several cell types produce cath- elicidins: keratinocytes, macrophages, mast cells, neutrophils, and eccrine glands [13]. Cathelicidins kill Gram-positive and Gram-negative bacteria and Trypanosoma cruzi. Similar to defensins, cathelicidins participate actively in linking innate and adaptive immunity and in modulating the amplitude of immune responses [14]. Expression pattern and gene regulation In general, mature, biologically active peptides require proteolytic cleavage from a precursor peptide [15]. The expression pattern of antimicrobial peptides is not uni- form across species, and within a species it is regulated by the cellular lineage, the differentiation ⁄ activation state of the cell, and the tissue type [16]. Some antimi- crobial peptides are synthesized in the absence of infec- tion or inflammation, whereas others are upregulated in response to endogenous or infectious ‘alarm’ signals, suggesting different functions for these peptides under different physiological settings. Moreover, differential proteolytic processing can modulate their activity and, by extension, their ability to modulate immunity [17]. Consequently, the combination of defense peptides produced by different cell types in a given tissue can positively or negatively modify cell functions, ulti- mately promoting bacterial clearance, albeit not neces- sarily through direct killing, but through the establishment of immune cell circuits. Defensins Genes for antimicrobial peptides tend to cluster within a chromosomal region. In the human genome, the genes encoding most human defensins are grouped within the same chromosomal region (8p21–23) [18], suggesting evolution from a single precursor gene as well as the existence of a master switch to orchestrate the synthesis of these molecules. However, the genes encoding the defensin family secreted in epididymis, testis, pancreas, kidney and skeletal muscle are located in chromosome 20. These peptides seem to be unique in the sense that they are only synthesized in those locations, and not in the skin or airways, the common sites for b-defensins, indicative of an as yet undiscov- ered biological function [19]. Interestingly, the number of defensin genes on chromosome 8 appears to fluc- tuate among individuals, partially explaining genetic susceptibility to infection [20]. Human a-defensins [human neutrophil peptides (HNPs) 1–4] are produced by leukocytes, Paneth cells of the small intestine, and epithelial cells of the female urogenital tract [1]. On stimulation through Toll-like receptor (TLR)-2, TLR-3, and TLR-5, neutrophils, NK cells and Paneth cells will release stored a-defen- sins to the extracellular milieu, where they will exert their antimicrobial activity. Interestingly, in addition to its antimicrobial capacity, a-defensin HNP1 has antiviral activity, as it inhibits HIV and influenza virus replication, following viral entry into target cells. It diminishes HIV replication by, on the one hand, block- ing steps subsequent to reverse transcription and inte- gration, and on the other by hindering a cellular protein kinase C-dependent mechanism that partici- pates in viral infection [21,22]. Similarly, it can inacti- vate herpes simplex virus, cytomegalovirus, vesicular stomatitis virus, and adenovirus [23]. Whether the molecular mechanisms that mediate these antiviral effects are common or virus-specific remains an open question. AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein 6498 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS Human b-defensins (hBDs) 1–4 show unique as well as overlapping expression patterns. The hBD-1 b-defensin is constitutively synthesized by epithelia that are in direct contact with the environment or microbial flora, such as lung, salivary gland, mammary gland, prostate, gut, as well as by leukocytes; it is upregulated by lipopolysaccharide (LPS) and peptidoglycan [24]. Although the expression pattern of hBD2 overlaps with that of hBD1, it is also present in skin, pancreas, leukocytes, and bone marrow. In addition to epithelia, hBD3 has been detected in nonepithelial cells, in the heart, liver, and placenta [4], and hBD4 mRNA has been detected in the testis, epididymis, lung tumor tis- sue [25], and gastric epithelial cells [26]. hBD1 and hBD2 have predominant antibacterial activity against Gram-negative bacteria and some fungi, whereas hBD3 has a broader spectrum and kills many patho- genic Gram-positive and Gram-negative bacteria and opportunistic yeasts such as Candida albicans [27]. b-Defensin expression is modulated in response to bacterial-derived molecules and ⁄ or to cytokines and chemokines produced by the immune system or dam- aged cells [16]. In keratinocytes stimulated by bacteria, interferon-c (IFN-c), tumor necrosis factor-a (TNF-a), interleukin (IL)-b, IL-17, or IL-22, hBD2 and hBD4 gene expression is upregulated, like that of hBD1 and hBD3 in airway, intestinal or uterine epithelial cells [28,29], whereas it is inhibited by retinoic acid [30] and heat shock [31]. In immune cells, their production is also upregulated following exposure to bacteria, LPS, IFN-c, or IL-b [29]. Cathelicidins The human cathelicidin gene is located on chromo- some 3 (3p21.3), in close proximity to the genes encod- ing TLR-9 and Myd88 (3p22). Cathelicidins are constitutively synthesized in thymus, spleen, bone mar- row, liver, skin, stomach, intestine, and testis. Besides epithelial cells, they are produced by neutrophils, monocytes, T-lymphocytes, B-lymphocytes, and NK cells. Upon epidermal injury, the concentration of human cathelicidin LL-37 is augmented significantly in keratinocytes and epidermal mast cells [32], and it has been detected in wound and blister fluid as well [33,34]. In keratinocytes, synthesis of LL-37 is induced in response to insulin-like growth factor 1, TNF-a [35], IL-1a, and IL-6 [36], and upon contact with Staphylo- coccus aureus [37]. Cathelicidin peptides have potent, direct antimicrobial activity against Gram-positive and Gram-negative bacteria and, importantly, against some antibiotic-resistant bacteria [38]. Conversely, virulence proteins of pathogenic microorganisms can negatively modulate the transcription of antimicrobial peptides, notably hBD-1 and LL-37 in intestinal epithelial cells [39], through a signaling pathway dependent on cAMP, protein kinase A, extracellular signal-related kinase, and Cox2 [40], counterbalancing the positive signals of alarmins. LL-37 was assumed to be the only active form of cathelicidin in the skin. However, LL-37 is susceptible to proteolytic processing, generating multiple cathelici- din-derived peptides that are present in normal human skin. LL-37 actually represents < 20% of the cathelic- idin-derived peptides, smaller forms of the peptide being more abundant. These smaller peptides result from proteolytic processing by two serine proteases belonging to the tissue kallicrein family: stratum corne- um tryptic enzyme (SCTE) (kallicrein-5) and stratum corneum chymotryptic enzyme (SCCE) (kallicrein-7). Based on its specificity, each enzyme generates a differ- ent set of peptides. SCTE generates three main pep- tides (KS30, KS22, and LL29), whereas the cleavage of LL-37 by SCCE yields two peptides (RK31 and KR20). SCTE is considered to be the generator of the cathelicidin-derived antimicrobial activity (KS30, KS22 and LL29 are very potent antimicrobial compounds, but lack chemotactic activity), and SCCE may be considered as the inactivator of LL-37, rather than a generator of antimicrobial peptides [17]. Ultimately, the relative proportions of these peptides may set the balance between antimicrobial activity and immuno- modulatory function. Expression of defensin-coding and cathelicidin-coding genes The final combination of peptides at a specific location reflects the signaling of pattern ⁄ pathogen-associated receptors as well as that of other molecules that sense the environmental conditions. A proof of this was pro- vided by experiments showing that frogs do not syn- thesize and produce the same combinations and relative proportions of antimicrobial peptides in a ster- ile environment as they do in their natural one. More- over, once they are pharmacologically depleted of antimicrobial peptides, frogs will not reaccumulate skin antimicrobial peptides until they are re-exposed to bacteria [41]. In agreement with the different environ- mental cues that promote antimicrobial peptide syn- thesis, multiple signaling pathways are involved. Upregulation of cathelicidin and defensin gene expres- sion in response to bacterial products and proinflam- matory molecules depends on the activation of the nuclear factor kappaB (NFjB), AP-1, JAK2 and STAT3 signaling pathways [16]. C. Auvynet and Y. Rosenstein AMPs, the small yet big players of immunity FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6499 Transcription of the human defensin (HD)5 and HD6 genes in Paneth cells is under the control of tran- scription factor-4 (TCF-4) (also named TCF7L2), a Wnt signaling pathway transcription factor, also involved in Paneth cell differentiation [42]. Reduced amounts of HD5 and HD6 peptides have been associ- ated with the development of Crohn’s disease [43,44]. Consistent with this, heterozygous TCF-4 knockout mice show decreased production of Paneth cell a-de- fensins and diminished bacterial killing capacity. The promoter region of neutrophil-derived defensins con- tains recognition sequences for transcription factors such as the hematopoietic-specific Ets family transcrip- tion factor PU.1 and C ⁄ EBP-a [16]), as well as an NFAT binding site overlapping the Pu.1 site. Interest- ingly, NFAT was found to be associated with the pro- moter in response to hepatitis C infection, thus suggesting a correlation between a-defensin expression and liver fibrosis [45]. In human skin, during wound healing, the synthesis of antimicrobial peptides by incoming neutrophils, and notably that of hBD-3, is induced through an LL-37-mediated mechanism of transactivation of the epidermal growth factor receptor [46]. The promoter regions of cathelicidin genes have consensus binding sites for NFjB, IL-6, acute phase response factor and IFN-c response element as well [16]. In mice, murine cathelin-related antimicrobial peptide (CRAMP) is dependent on hypoxia-inducible factor-1a, a factor now understood to play a key role in the bactericidal capacity of phagocytic cells such as macrophages and neutrophils [47]. In different human cell types (keratinocytes, monocytes, neutrophils, and bone marrow-derived macrophages), cathelicidin gene expression is under the control of vitamin D-respon- sive elements [48]. In turn, upregulation of the vita- min D receptor (VDR) and Cyp27B1, the enzyme that catalyzes the conversion of 25-hydroxyvitamin D 3 to the active 1,25-hydroxyvitamin D 3 , is depen- dent on TLR-mediated signals. Moreover, 1,25-hy- droxyvitamin D 3 increases CD14 and TLR-2 synthesis. All together, these data reveal a direct link between 1,25-hydroxyvitamin D 3 , TLR activation, the VDR and downstream targets such as cathelicidin, ultimately regulating the antibacterial response [49]. Interestingly, many autoimmune patients are deficient in vitamin D, and providing greater quantities of it reduces the symptoms [50]. Likewise, VDR-deficient mice or vitamin D-deficient mice show increased sen- sitivity to autoimmune diseases such as inflammatory bowel disease and type I diabetes [51]. Whether there is a direct connection between low levels of 1,25-di- hydroxyvitamin D 3 , low levels of cathelicidin produc- tion, poor clearance of bacterial pathogens and autoimmunity is certainly a challenging concept that needs to be further investigated. A recent computational analysis of the promoter region of 61 genes belonging to 29 families of mouse, rat and human antimicrobial peptide-encoding genes identified factors that regulate the transcription of anti- microbial peptides. In addition to predicting most of the transcription factors already described individually for antimicrobial peptides, this study suggests that the influence of the VDR and new nuclear hormone recep- tors (glucocorticoid receptor, retinoic receptor, etc.) is not restricted to cathelicidins, and that it extends to other antimicrobial peptides, in particular a-defensins. Furthermore, this in silico study identified a core set of transcription factors regulating the transcription of the majority of antimicrobial peptides considered. The transcription factors were grouped in tissue specific- categories, of which the liver-specific, neuron-specific and nuclear hormone-specific factors occupied the first positions, underscoring new functions for antimicrobial peptides in energy metabolism and neuroendocrine regulation [52], in addition to their role in immunity. Immunomodulatory properties of antimicrobial peptides By disrupting bacterial membranes, antimicrobial pep- tides participate as direct effectors of innate immunity. Multiple antimicrobial peptides are simultaneously present at the same site, and they are thought to work in concert, to effectively fight infection. It has frequently been argued that the minimal inhibitory con- centration of antimicrobial peptides needed to effec- tively combat microbial infection is rarely found in in vivo conditions, despite the fact that antimicrobial peptide gene expression is mostly under the control of innate immunity-related transcription factors. However, in addition to the concentration of these natural antibi- otics, the resistance of the microbial membrane (i.e. the target of the antimicrobial peptides) in a given ionic environment is the counterpart to effectiveness of anti- microbial activity. In support of this, it has recently been shown that S. aureus and Escherichia coli grown in carbonate-containing solutions are more susceptible to physiological concentrations of antimicrobial pep- tides, as a result of changes in bacterial gene expression that translate into changes in cell wall thickness and the expression of several genes related to virulence [53]. Thus, the balance in the host’s ionic condition is an important element to consider when evaluating the antimicrobial activity of a given peptide. Also, it should be considered that the microbicidal activity of most AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein 6500 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS antimicrobial peptides is very potent in the intracellular compartment, in phagocytic vacuoles, and on the exter- nal surface of skin and mucosa, three low-salt compart- ments. Updating the molecular mechanisms involved in this microbicidal effect is beyond the scope of this minireview, but it is a field of extensive research. Innate immunity cells such as neutrophils, mast cells and eosinophils can form extracellular traps (ETs) that consist of a chromatin–DNA backbone, to which anti- microbial peptides and enzymes are attached, ultimately forming a net in which microbes are entrapped and killed [54]. An NAPDH oxidase-dependent mechanism initiates a signaling cascade that leads to the disintegra- tion of the nuclear and cellular membrane [55], leading to cell death and the formation of ETs. Besides augmenting the local concentration of antimicrobial peptides and effectively killing the microbes, it is possi- ble to think that ETs limit the diffusion of microbe- derived alarmins, minimizing tissue damage. Data from experiments with knockout and trans- genic mice highlight the direct antimicrobial effect of antimicrobial peptides [7,16]. However, given the cen- tral role that antimicrobial peptides seem to play in the outcome of an infection ⁄ injury, it is surprising to see that all knockout mice lacking antimicrobial pep- tides are quite healthy, with only modest alterations in susceptibility to specific infectious agents. For example, mice lacking b-defensin-1 are inefficient at clearing Haemophilus influenzae from their lungs [56], and CRAMP-deficient mice are impaired in their ability to clear skin infections caused by group A Streptococcus [57]. These results underline the fact that antimicrobial peptides work in concert, and that their ranges of activity frequently overlap. Apart from efficient antimicrobial activity, antimi- crobial peptides modulate immunity. They seem to participate in every facet of it, by boosting the immune response to prevent infection, and also by suppressing other proinflammatory responses to avoid uncontrolled inflammation. Furthermore, some antimicrobial pep- tides synergize with cytokines and modify their immuno- modulatory activity. Chemotactic activity In addition to their direct microbicidal activity, antimi- crobial peptides are chemotactic for leukocytes and other nonimmune cells at nanomolar concentrations. Despite a certain overlap, antimicrobial peptides work in concert, as they complement each other to direct effector cells to the site of inflammation, organizing the order of appearance of the different players in different scenarios, and modulating the local immune response. Phagocytic cells, neutrophils and monocytes that are recruited through a-defensins, HNP1–3 and b-defen- sins hBD3 and hBD4, and mast cells that are attracted through LL-37, HNP1–3 and hBD2 contribute to increase the local density of neutrophils [58]. In addi- tion, hBD1 and hBD3 are chemotactic for immature dendritic cells and memory T-cells, whereas human a-defensins selectively induce the migration of human naı ¨ ve CD4 + CD45 + and CD8 + cells [7]. The combina- tion of these peptides and cytokines present at the site of injury will contribute to the maturation of these immature dendritic cells, enabling them to process antigen and to migrate to proximal lymph nodes to present antigens to naı ¨ ve cells, thus setting in motion the adaptive immune response machinery, and shaping the outcome of the response. Besides their intrinsic chemoattractant properties, which directly promote the locomotion and arrival of different cohorts of cells to the site of injury, antimicrobial peptides indirectly favor chemotaxis by inducing or increasing the secre- tion of chemokines. For example, LL-37 has been shown to induce IL-8 release by lung epithelial cell lines [59,60], and human defensins HNP1–3 also favor the recruitment of neutrophils by inducing the activa- tion and degranulation of mast cells, augmenting neu- trophil influx and further stimulating the transcription and production of IL-8 by bronchial epithelial cells [61–64]. Antimicrobial peptide-induced chemotaxis is pre- sumably mediated through G-protein-coupled recep- tors, as pretreatment of the cells with pertussis toxin or phospholipase C, phosphoinositide-3-kinase and Rho kinase inhibitors abolishes cell migration [65]. According to the peptide and the cell, several receptors have been identified. LL-37, like the frog peptides tem- porin A and probably Drs S9, attracts cells through formyl peptide receptor-like-1, whereas defensins hBD2 and hBD3 use CC-chemokine receptor-6, pres- ent on memory T-cells, immature dendritic cells, and human colonic epithelial cells [66–69]. CC-chemokine receptor-6 is also the receptor for macrophage inflam- matory protein-3a, a chemokine involved in homeo- static lymphocyte homing as well as in epithelial cell migration, further suggesting a function for hBD2 in healing and protection of the intestinal epithelial barrier [70]. Proinflammatory and anti-inflammatory signals of antimicrobial peptides Antimicrobial peptides have a dual identity: they pro- tect the host against potentially harmful pathogens through their antimicrobial activity and by stimulating C. Auvynet and Y. Rosenstein AMPs, the small yet big players of immunity FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6501 innate immune functions, yet, at the same time, they protect the organism from the detrimental effects of an excessive inflammatory response. In addition to their direct antimicrobial capacity, the in vivo contribution of antimicrobial peptides to anti- microbial defense depends on their capacity to induce the production of proinflammatory cytokines, to pro- mote the recruitment of dendritic cells and monocytes to the site of injury, and to enhance phagocytosis and the maturation of dendritic cells. All of these effects will augment the uptake, processing and presentation of antigen, and stimulate the clonal expansion of T-lymphoctes and B-lymphocytes. B-lymphocytes will produce antibodies that are highly specific for patho- gen antigens, contributing to the clearance of microbes through phagocytosis [16]. Some of the molecular mechanisms that control this positive feedback loop have been described recently. Human a-defensins and b-defensins induce the release of histamine and prostaglandin D 2 in a G-protein– phospholipase C-dependent manner [62] [71]; HPN1–3 bind C1q and activate the classic complement pathway [72], increase the production of TNF-a and IL-1b, and decrease the production of IL-10 by monocytes [61,62,73]. Furthermore, as an endogenous ligand for TLR-4, b-defensin-2 activates immature dendritic cells through TLR-4-dependent mechanisms, triggering a robust Th1 response [74]. Consistent with their role in wounding, b-defensin-mediated signals positively regu- late the expression of matrix metalloproteinase genes and negatively regulate that of tissue inhibitor of matrix metalloproteinase genes, thus modulating tissue repair [75,76]. LL-37 induces the release of IL-1b, IL- 8, TNF-a, IL-6 and granulocyte–macrophage colony- stimulating factor (GM-CSF) by keratinocytes, and of TNF-a and IL-6 by immature dendritic cells [58,77]. Moreover, LL-37 and GM-CSF synergize, as the pres- ence of GM-CSF augments LL-37-mediated mitogen- activated protein kinase activation and reduces the amount of LL-37 required for this activation and for cytokine production [78,79]. Cathelicidins function as anti-inflammatory mole- cules as well. In in vivo models, administration of LL-37 protects mice and rats from LPS-mediated lethality [60,80]. Indeed, LL-37 binds and neutralizes LPS, possibly by dissociation of LPS aggregates, limit- ing the extent of inflammation [60,81–84]. Addition- ally, cathelicidin abrogates the expression of proinflammatory molecules such as TNF-a and IL-6 and the nuclear translocation of NFjB p50 ⁄ p65 induced by TLR-2 and TLR-4 in response to lipoteic acid and LPS, respectively, through a partially defined mechanism involving mitogen-activated protein kinase p38 inactivation [85]. This immunomodulatory effect of the TLR response is mediated through the binding of the mid-region of LL-37, comprising amino acids 13–31, to TLR ligands through an LPS-binding mech- anism [86]. Moreover, LL-37 was found to selectively permeabilize the membranes of apoptotic human leukocytes through a mechanism similar to the direct microbicidal effect, independently of known surface receptors or cell signaling, leaving viable cells un- affected. This causes the cells to empty the cytoplasm as well as intragranular molecules to the extracellular compartment, shifting the balance between proinflam- matory and anti-inflammatory signals [87]. Further- more, the fact that, as mentioned, LL-37 is shortened by a serine protease-dependent mechanism, generating novel antimicrobial peptides with enhanced antimicro- bial action, but reduced proinflammatory activity, con- tributes to controlling the inflammatory response [88]. In addition, these data point to the role of hydropho- bicity in the immunomodulatory capacity of LL-37 [86] and potentially in new synthetic peptides designed to downmodulate inflammatory responses. Accord- ingly, IDR-1, a synthetic peptide derived from LL-37, although devoid of direct antimicrobial activity, is effective in limiting a broad range of Gram-positive and Gram-negative pathogens, through signaling path- ways that increase the level of monocyte cytokines while diminishing proinflammatory responses [89]. Such peptides, capable of suppressing the host’s harm- ful proinflammatory responses without losing the beneficial infection-fighting components of host innate defenses, are desirable tools for antisepsis therapies. Defensins play the same dual role as cathelicidins. The activation of TLR-4, mediated through murine b-defensin-2, leads to atypical death of dendritic cells, through upregulation of membrane-bound TNF-a and tumor necrosis factor receptor 2. This suggests that b-defensins participate in the triggering of an immune response and in the natural process of elimination of activated antigen-presenting cells and termination of the immune response [90]. Healing Infection and injury provoke tissue damage. Immedi- ately after injury, innate immune cells, mostly neu- trophils and macrophages, together with antimicrobial peptides, produced by immune cells or secreted by local cells, will take care of microbe clearance and removal of debris. Other cells, such as T-lymphocytes, secrete cytokines and chemokines that will further activate macrophages and induce inflammation and vasodilatation, and enhance vessel permeability. Tissue AMPs, the small yet big players of immunity C. Auvynet and Y. Rosenstein 6502 FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS regeneration requires multiple events. Following removal of bacteria and debris, the release of growth factors will promote the migration and proliferation of fibroblasts, which will deposit the extracellular matrix over which epithelial cells will crawl and cover the wound bed [91]. A recent report showed the secretion of hBD3 and other antimicrobial peptides by human keratinocytes, after the disappearance of neutrophils and before the re-establishment of the physical barrier, in sterile wounds as well as in microbe-induced wounds [35,46]. The expression of antimicrobial peptides at that time is probably protective against subsequent infections. However, the fact that growth factors such as IGF-1, transforming growth factor-a, and epidermal growth factor, in combination with IL-1, induce the secretion of LL-37, hBD3 and other antimicrobial peptides by human keratinocytes [35,59] suggests that antimicro- bial peptides participate in additional tasks. LL-37 is mostly present in the inflammatory infiltrate as well as in the epithelium migrating over the wound, but not at the wound edge. Interestingly, its highest level in the skin wounds is reached 48 h postinjury, whereas the normal level is achieved only upon wound closure, after infection resolution, suggesting direct participa- tion of LL-37 in wounding [92]. Indeed, through trans- activation of epidermal growth factor receptor, LL-37 induces keratinocyte migration [93], and through for- myl peptide receptor-like-1, it induces angiogenesis [94]. Consistent with this role in wound healing, and in addition to increased bacterial colonization, mice lack- ing the cathelicidin gene have longer periods of wound healing than their wild-type counterparts [57,95]. Simi- larly, hBD-2 was recently described as also being a potent promoter of human endothelial cell migration, proliferation and, in the presence of angiogenic factors, tube formation [96], accelerating wound closure. LL-37 may also have antifibrotic activity during the wound repair process, as it inhibits baseline and transforming growth factor-b-induced collagen expression at nanom- olar concentrations, through an extracellular signal- related kinase-dependent and G-protein-dependent pathway [97]. These data regarding the role of antimicrobial pep- tides in wounding provide evidence for their dual role; they serve as sentinels and they actively participate in tissue regeneration. Whether noninducible antimicro- bial peptides function in a similar way during infec- tion, under normal conditions or during development is an attractive possibility. In conclusion, the multiple, yet sometimes opposite, functions of antimicrobial peptides are complementary, and they control homeo- stasis through complex regulatory loops that involve different cells responding to multiple signaling path- ways. Antimicrobial peptides and disease Dysregulated production of antimicrobial peptides is associated with disease. As we recognize that these molecules are multifunctional and that they modulate multiple events, the list of diseases in which anti- microbial peptides participate is growing. Throughout previous sections of this minireview, we have pointed to the participation of antimicrobial peptides in several diseases. In this section, we will highlight recent data on psoriasis, rosacea, atopic dermatitis and Crohn’s disease. It was long considered that skin passively obstructed the entrance of pathogens, thus constituting a natural barrier against potential microbial pathogens and other assaults from the external environment. It is now clear that, through the antimicrobial activity and inmuno- modulatory functions of antimicrobial peptides, the skin plays a major and active role in the onset and development of an immune response to injury and microbial insult. Recent publications have narrowed the role of cathelicidins and defensins in psoriasis, ros- acea and atopic dermatitis, providing evidence that the concentration, processing and signaling of antimicro- bial peptides are critical parameters for maintaining the delicate equilibrium between effective protection and autoimmunity. As mentioned, cathelicidin and hBD1–4 are present in low amounts in healthy skin keratinocytes, but in response to injury or infection, their synthesis is signifi- cantly enhanced [98]. In atopic dermatitis, the continu- ous bacterial and viral infections produce chronic inflammation. It was recently shown that the cytokine milieu (IL-4 and IL-13) of this Th2-type inflammatory skin disease downregulates the gene expression of LL- 37, and thus contributes to a partially uncontrolled cutaneous innate immune response in those patients [99]. A recent report showed that Bcl-3, a protein with close homology to IjB proteins and that interacts with p50 NFjB homodimers, is overexpressed in skin lesions of patients with atopic dermatitis, and that its silencing reverses the inhibitory effect of IL-4 on hBD3 gene expression. Moreover, Bcl-3 silencing upregulates the 1,25-dihydroxyvitamin D 3 -dependent production of cathelicidin in keratinocytes, and 1,25-dihydroxyvita- min D 3 suppresses Bcl-3 expression [100]. In addition, Bcl-3 synthesis is upregulated in the presence of IL-4 [101], thus generating a negative feedback loop that will reduce the cathelicidin concentration, favoring skin infections and chronic inflammation. C. Auvynet and Y. Rosenstein AMPs, the small yet big players of immunity FEBS Journal 276 (2009) 6497–6508 ª 2009 The Authors Journal compilation ª 2009 FEBS 6503 Unlike atopic dermatitis, psoriasis, a common auto- immune disease of the skin, results partially cathelici- din overproduction. By binding to damaged or apoptotic skin cells self-DNA, cathelicidin converts it into aggregated and condensed structures. That will be delivered to plasmocytoid dendritic cells. These, in turn, will infiltrate the psoriatic skin, triggering en- dosomal TLR-9 and subsequent IFN-c production, thus driving autoimmune skin inflammation [102]. Patients with rosacea have abnormal inflammation and vascular reactivity in facial skin. These individuals have high levels of cathelicidin and higher levels of the enzyme that processes the propeptide into the LL-37 biologically active peptide and of other unusual iso- forms of the peptide. The current thinking is that, at least partially, the chronic inflammation results from the increased chemotactic and angiogenic activity of the LL-37-derived peptides [103]. Crohn’s disease is an inflammatory disease of the small intestine and ⁄ or the colon. As mentioned already, in the small intestine, the pathogenesis is asso- ciated with a reduced expression of the Wnt signaling pathway TCF-4, involved in Paneth cell differentiation and in a-defensin gene expression [42]. Consequently, a-defensin-2 and a-defensin-3 genes are deficiently expressed, regardless of the inflammation. Moreover, single-nucleotide polymorphisms in TCF-4 are directly related to ileal Crohn’s disease incidence, providing evidence that low levels of HD5 and HD6 are directly associated with the disease [43]. In contrast, in the colon, Crohn’s disease is associated with impaired expression of the genes encoding hBD5 and hBD6. Patients affected with this form of disease tend to have fewer gene copy numbers in the locus of b-defensin in chromosome 8. As a result of this deficiency in a-de- fensins and b-defensins, luminal microbes invade the mucosa and trigger inflammation [104]. Concluding remarks Initially described as molecules with bactericidal capac- ity, antimicrobial peptides are now considered to be multifunctional molecules. They stimulate the produc- tion and release of proinflammatory and anti-inflam- matory molecules, they recruit inflammatory cells to the site of injury, they function as antimicrobial mole- cules directly and by promoting ingestion of microbes by phagocytic cells, and they participate in damage repair. These pleiotropic effects reflect the diversity of effector molecules and their targets, as well as the sometimes overlapping, yet very specific, functions. Through elaborate feedback mechanisms, they control immune cells as well as nonimmune cells, link innate immunity to adaptive immunity, and maintain homeo- stasis. Alterations in their physiological concentrations correlate with disease. 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MINIREVIEW Multifunctional host defense peptides: Antimicrobial peptides, the small yet big players in innate and adaptive immunity Constance. mediators in the crosstalk between the innate and adaptive immune systems [4]. In addition to a highly conserved cathelin domain, cathelicidins have an N-terminal