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Potential of immunomodulatory host defense peptides as novel anti-infectives

2009; Elsevier BV; Volume: 27; Issue: 10 Linguagem: Inglês

10.1016/j.tibtech.2009.07.004

0167-9430

Donna M. Easton, Anastasia Nijnik, Matthew L. Mayer, Robert E. W. Hancock,

Viral gastroenteritis research and epidemiology

A fundamentally new strategy for the treatment of infectious disease is the modulation of host immune responses to enhance clearance of infectious agents and reduce tissue damage due to inflammation. Antimicrobial host defense peptides have been investigated for their potential as a new class of antimicrobial drugs. Recently their immunomodulatory activities have begun to be appreciated. Modulation of innate immunity by synthetic variants of host defense peptides, called innate defense regulators (IDRs), is protective without direct antimicrobial action. We discuss the potential and current limitations in exploiting the immunomodulatory activity of IDRs as a novel anti-infective pathway. IDRs show significant promise and current research is uncovering mechanistic information that will aid in the future development of IDRs for clinical use. A fundamentally new strategy for the treatment of infectious disease is the modulation of host immune responses to enhance clearance of infectious agents and reduce tissue damage due to inflammation. Antimicrobial host defense peptides have been investigated for their potential as a new class of antimicrobial drugs. Recently their immunomodulatory activities have begun to be appreciated. Modulation of innate immunity by synthetic variants of host defense peptides, called innate defense regulators (IDRs), is protective without direct antimicrobial action. We discuss the potential and current limitations in exploiting the immunomodulatory activity of IDRs as a novel anti-infective pathway. IDRs show significant promise and current research is uncovering mechanistic information that will aid in the future development of IDRs for clinical use. Infectious diseases remain a leading cause of death and a major burden on healthcare systems worldwide [1Rappuoli R. From Pasteur to genomics: progress and challenges in infectious diseases.Nat. Med. 2004; 10: 1177-1185Crossref PubMed Scopus (93) Google Scholar]. For example, the HIV pandemic continues to claim two million lives per year, with an estimated 33 million people living with HIV/AIDS worldwide [2WHO (2008) World Health Statistics 2008, World Health Organisation PressGoogle Scholar] and novel human pathogens, such as the severe acute respiratory syndrome (SARS) associated coronavirus and H5N1 avian influenza, have recently emerged [3Weiss R.A. McMichael A.J. Social and environmental risk factors in the emergence of infectious diseases.Nat. Med. 2004; 10: S70-76Crossref PubMed Scopus (465) Google Scholar]. Other infectious diseases, including tuberculosis and diarrhoreal disease, remain among the leading causes of death [2WHO (2008) World Health Statistics 2008, World Health Organisation PressGoogle Scholar]. Dangers are also posed by the spread of infectious agents to new geographic locations, as exemplified by the recent cases of West Nile virus infection in North America [3Weiss R.A. McMichael A.J. Social and environmental risk factors in the emergence of infectious diseases.Nat. Med. 2004; 10: S70-76Crossref PubMed Scopus (465) Google Scholar]. In addition, the rapid evolution of antibiotic resistance in many bacterial pathogens creates an urgent need for new antimicrobial drugs and strategies for the treatment of infectious diseases [4Spellberg B. et al.The epidemic of antibiotic resistant infections: a call to action for the medical community from the Infectious Diseases Society of America.Clin. Infect. Dis. 2008; 46: 155-164Crossref PubMed Scopus (1273) Google Scholar]. Our rapidly expanding knowledge of the immune system is creating new opportunities for the development of immunomodulatory therapies [5Waldmann T.A. Immunotherapy: past, present and future.Nat. Med. 2003; 9: 269-277Crossref PubMed Scopus (521) Google Scholar, 6Hamill P. et al.Novel anti-infectives: is host defence the answer?.Curr. Opin. Biotechnol. 2008; 19: 628-636Crossref PubMed Scopus (74) Google Scholar]. Unlike conventional antibiotics that are designed to target a pathogen, such therapies exert their protective effects by acting on the host immune system. Many therapies designed to target the immune system have entered clinical use in recent decades and many more are progressing through clinical trials. These include immunosuppressive therapeutics for use in tissue transplantation, autoimmune and inflammatory conditions and compounds designed to stimulate immune responses, for example vaccine adjuvants. Although a wide variety of compounds are under investigation, most therapeutics approved to date belong to one of the following classes: monoclonal antibodies, Toll-like receptor (TLR) ligands and their derivatives, cytokines and chemokines, and small molecules. Monoclonal antibodies are used clinically to stimulate and block cell-surface receptors, inactivate cytokines and other molecules in circulation and deliver antigens to dendritic cells or direct toxins towards tumor cells [5Waldmann T.A. Immunotherapy: past, present and future.Nat. Med. 2003; 9: 269-277Crossref PubMed Scopus (521) Google Scholar]. TLR ligands are used for their immunostimulatory activities [7Romagne F. Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors.Drug Discov. Today. 2007; 12: 80-87Crossref PubMed Scopus (76) Google Scholar, 8Kanzler H. et al.Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists.Nat. Med. 2007; 13: 552-559Crossref PubMed Scopus (744) Google Scholar]. For example, the TLR4 ligand monophosphoryl lipid-A (MPL) is used as an adjuvant in vaccines against hepatitis B virus (HBV) and human papillomavirus (HPV) [9Pashine A. et al.Targeting the innate immune response with improved vaccine adjuvants.Nat. Med. 2005; 11: S63-68Crossref PubMed Scopus (463) Google Scholar, 10Harper D.M. et al.Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.Lancet. 2006; 367: 1247-1255Abstract Full Text Full Text PDF PubMed Scopus (1445) Google Scholar]. In addition, the TLR7 agonist imiquimod is approved as a topical treatment for HPV-induced genital warts and for basal cell carcinoma. Various compounds designed to stimulate TLR3, TLR5, TLR7/8 and TLR9 are also undergoing clinical trials, primarily as adjuvants in vaccines against chronic viral infections or as adjuncts in cancer chemotherapy [7Romagne F. Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors.Drug Discov. Today. 2007; 12: 80-87Crossref PubMed Scopus (76) Google Scholar, 8Kanzler H. et al.Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists.Nat. Med. 2007; 13: 552-559Crossref PubMed Scopus (744) Google Scholar]. Immunotherapeutic use of cytokines, chemokines and hormones is exemplified by type-I interferons for the treatment of chronic HBV infections, granulocyte monocyte-colony stimulating factor (GM-CSF) for the treatment of neutropenia and glucocorticoids for the treatment of asthma and other chronic inflammatory diseases [11Viola A. Luster A.D. Chemokines and their receptors: drug targets in immunity and inflammation.Annu. Rev. Pharmacol. Toxicol. 2008; 48: 171-197Crossref PubMed Scopus (470) Google Scholar]. A common application of small molecules is to target intracellular signal transduction pathways [12O'Neill L.A. Targeting signal transduction as a strategy to treat inflammatory diseases.Nat. Rev. Drug Discov. 2006; 5: 549-563Crossref PubMed Scopus (244) Google Scholar]. For example, organ transplant rejection can be limited by inhibiting the mammalian target of rapamycin (mTOR) with rapamycin or by inhibiting calcineurin with cyclosporine and FK506, thus reducing T-cell signal transduction. Many other small molecules that target components of pathways, such as those involving nuclear factor κB (NFκB), p38 mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducers and activators of transcription (JAK-STAT), are also undergoing clinical trials [12O'Neill L.A. Targeting signal transduction as a strategy to treat inflammatory diseases.Nat. Rev. Drug Discov. 2006; 5: 549-563Crossref PubMed Scopus (244) Google Scholar]. Adoptive transfers of dendritic cells [13Figdor C.G. et al.Dendritic cell immunotherapy: mapping the way.Nat. Med. 2004; 10: 475-480Crossref PubMed Scopus (875) Google Scholar] and autologous cytotoxic T-cells [14Rosenberg S.A. et al.Adoptive cell transfer: a clinical path to effective cancer immunotherapy.Nat. Rev. Cancer. 2008; 8: 299-308Crossref PubMed Scopus (1315) Google Scholar], which are effective therapies for some forms of cancer, can also be considered immunotherapies. Although many immunotherapies have been approved for use in the clinic and many others have shown efficacy in clinical trials, there are a number of obstacles that prevent their widespread use. The use of immunosuppressive therapies is often associated with increased risk of infections and might also predispose individuals to cancer [15Dinarello C.A. Anti-cytokine therapeutics and infections.Vaccine. 2003; 21: S24-34Crossref PubMed Scopus (136) Google Scholar, 16Askling J. Bongartz T. Malignancy and biologic therapy in rheumatoid arthritis.Curr. Opin. Rheumatol. 2008; 20: 334-339Crossref PubMed Scopus (68) Google Scholar]. Immunostimulatory treatments can result in inflammatory tissue damage, autoimmunity or potentially fatal cytokine storms [17Ponce R. Adverse consequences of immunostimulation.J. Immunotoxicol. 2008; 5: 33-41Crossref PubMed Scopus (33) Google Scholar, 18Suntharalingam G. et al.Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.N. Engl. J. Med. 2006; 355: 1018-1028Crossref PubMed Scopus (1790) Google Scholar]. These risks limit the application of most immunotherapies to life-threatening conditions for which better-tolerated treatments are not available. It is increasingly recognized that most conditions will not be treatable through generic stimulation or suppression of the immune system, as demonstrated by the failures of immunosuppressive therapies for sepsis [19O'Callaghan A. Redmond H.P. Treatment of sepsis: current status of clinical immunotherapy.Surgeon. 2006; 4: 355-361Abstract Full Text PDF PubMed Scopus (9) Google Scholar]. Hence, we need to develop tools that precisely control, modulate and/or polarize the immune response. To be commercially viable, ideal therapies also need to be broad-spectrum and target a class of related conditions or pathogens. These challenges highlight the importance of studying the immune system from a systems biology perspective to predict the outcome and efficacy of immunomodulatory therapies [20Schadt E.E. et al.A network view of disease and compound screening.Nat. Rev. Drug Discov. 2009; 8: 286-295Crossref PubMed Scopus (248) Google Scholar, 21Brown K.L. et al.Complexities of targeting innate immunity to treat infection.Trends Immunol. 2007; 28: 260-266Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. This is discussed further in Box 1.Box 1Systems biology approaches to studying immunomodulatory activityDrug development and complex systemsThe innate immune system is a very complex, non-linear network for which there is great potential for subtle manipulations of signaling pathways and subsequent changes in cytokine production with far-reaching downstream effects that might be beneficial but are not completely predictable, desirable or controllable [21Brown K.L. et al.Complexities of targeting innate immunity to treat infection.Trends Immunol. 2007; 28: 260-266Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. As recently discussed by Schadt et al. [20Schadt E.E. et al.A network view of disease and compound screening.Nat. Rev. Drug Discov. 2009; 8: 286-295Crossref PubMed Scopus (248) Google Scholar], progress in drug discovery and development requires an integrated approach that takes into account the non-linear causal relationships inherent in complex systems. This concept applies particularly to immunomodulation because of the significant cross-talk between pathways in the immune system. It is not possible to model the entire innate immune system either in vitro or computationally; however, systems biology approaches can aid in the understanding of complex interactions and signaling pathways. Attempts to understand the likely effects of immunmodulatory drugs require an appreciation of associated interactions within the immune system as a whole and their effects on other major systems, such as metabolism and hormonal and neuronal pathways.Computational aids to systems biology approachesThere are many freely available and commercial bioinformatics tools and databases for data-mining and analysis of many aspects of biological systems. Of particular interest to the development of immunomodulatory drugs are those that include the following:•Interactome data specific to innate immunity, such as InnateDB (www.innatedb.com), a manually curated database and analysis platform for the genes, proteins, interactions, pathways and signaling responses in human and mouse innate immune responses;•Immunology-specific information, especially for immune-relevant transcriptome analysis, such as the Innate Immunity Database (http://db.systemsbiology.net/IIDB);•Pathway interaction data, such as the NCI-Nature Pathway Interaction Database (http://pid.nci.nih.gov); and•Tools for specific protein interaction analysis, such as IntAct (http://www.ebi.ac.uk/intact/).The development and use of InnateDB [51Lynn D.J. et al.InnateDB: facilitating systems-level analyses of the mammalian innate immune response.Mol. Syst. Biol. 2008; 4: 218Crossref PubMed Scopus (296) Google Scholar], which integrates data from many other freely available databases and has manually curated interaction information, analysis tools and visualization capability, has provided an insight into the signaling pathways and potential downstream effects of peptide treatments. For example, we recently reported the application of such an approach to study LL-37, with experimental verification of bioinformatics predictions [52Mookherjee N. et al.Systems biology evaluation of immune responses induced by human host defence peptide LL-37 in mononuclear cells.Mol. Biosyst. 2009; 5: 483-496Crossref PubMed Scopus (90) Google Scholar]. Conceivably, such a system could be used in conjunction with gene array or proteomics data to aid in the iterative rational design and testing of immunomodulatory peptides by analyzing how individual peptides influence different pathways. Pathway and ontology analyses can also implicate specific biological processes in the activity of these peptides. The innate immune system is a very complex, non-linear network for which there is great potential for subtle manipulations of signaling pathways and subsequent changes in cytokine production with far-reaching downstream effects that might be beneficial but are not completely predictable, desirable or controllable [21Brown K.L. et al.Complexities of targeting innate immunity to treat infection.Trends Immunol. 2007; 28: 260-266Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. As recently discussed by Schadt et al. [20Schadt E.E. et al.A network view of disease and compound screening.Nat. Rev. Drug Discov. 2009; 8: 286-295Crossref PubMed Scopus (248) Google Scholar], progress in drug discovery and development requires an integrated approach that takes into account the non-linear causal relationships inherent in complex systems. This concept applies particularly to immunomodulation because of the significant cross-talk between pathways in the immune system. It is not possible to model the entire innate immune system either in vitro or computationally; however, systems biology approaches can aid in the understanding of complex interactions and signaling pathways. Attempts to understand the likely effects of immunmodulatory drugs require an appreciation of associated interactions within the immune system as a whole and their effects on other major systems, such as metabolism and hormonal and neuronal pathways. There are many freely available and commercial bioinformatics tools and databases for data-mining and analysis of many aspects of biological systems. Of particular interest to the development of immunomodulatory drugs are those that include the following:•Interactome data specific to innate immunity, such as InnateDB (www.innatedb.com), a manually curated database and analysis platform for the genes, proteins, interactions, pathways and signaling responses in human and mouse innate immune responses;•Immunology-specific information, especially for immune-relevant transcriptome analysis, such as the Innate Immunity Database (http://db.systemsbiology.net/IIDB);•Pathway interaction data, such as the NCI-Nature Pathway Interaction Database (http://pid.nci.nih.gov); and•Tools for specific protein interaction analysis, such as IntAct (http://www.ebi.ac.uk/intact/).The development and use of InnateDB [51Lynn D.J. et al.InnateDB: facilitating systems-level analyses of the mammalian innate immune response.Mol. Syst. Biol. 2008; 4: 218Crossref PubMed Scopus (296) Google Scholar], which integrates data from many other freely available databases and has manually curated interaction information, analysis tools and visualization capability, has provided an insight into the signaling pathways and potential downstream effects of peptide treatments. For example, we recently reported the application of such an approach to study LL-37, with experimental verification of bioinformatics predictions [52Mookherjee N. et al.Systems biology evaluation of immune responses induced by human host defence peptide LL-37 in mononuclear cells.Mol. Biosyst. 2009; 5: 483-496Crossref PubMed Scopus (90) Google Scholar]. Conceivably, such a system could be used in conjunction with gene array or proteomics data to aid in the iterative rational design and testing of immunomodulatory peptides by analyzing how individual peptides influence different pathways. Pathway and ontology analyses can also implicate specific biological processes in the activity of these peptides. Host defense peptides (HDPs) (also known as antimicrobial peptides) are being investigated as potential immunotherapeutic agents because of to their unique combination of immunostimulatory and anti-inflammatory properties [6Hamill P. et al.Novel anti-infectives: is host defence the answer?.Curr. Opin. Biotechnol. 2008; 19: 628-636Crossref PubMed Scopus (74) Google Scholar, 22Hancock R.E.W. Sahl H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies.Nat. Biotechnol. 2006; 24: 1551-1557Crossref PubMed Scopus (3326) Google Scholar]. HDPs are produced by the immune systems of all multicellular organisms and are extremely diverse from the perspectives of both sequence and structure. Despite this diversity, most peptides are amphipathic molecules, with an overall net positive charge, and a high content of cationic and hydrophobic amino acids. Classes of peptides such as cathelicidins [23Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity.J. Leukoc. Biol. 2004; 75: 39-48Crossref PubMed Scopus (868) Google Scholar], defensins [24Ganz T. Defensins: antimicrobial peptides of innate immunity.Nat. Rev. Immunol. 2003; 3: 710-720Crossref PubMed Scopus (2465) Google Scholar] and histatins [25Kavanagh K. Dowd S. Histatins: antimicrobial peptides with therapeutic potential.J. Pharm. Pharmacol. 2004; 56: 285-289Crossref PubMed Scopus (149) Google Scholar] are distinguished by their sequence, structure or mechanism of production. The general characteristics of cathelicidins and defensins are described in Box 2. In mammals these peptides are primarily produced by leukocytes, mucosal epithelial cells and keratinocytes.Box 2Mammalian host defense peptidesCathelicidins are cationic amphipathic peptides of diverse linear, α-helical or β-hairpin structure and are produced by proteolysis of the C-terminus of cathelin-domain-containing protein precursors [23Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity.J. Leukoc. Biol. 2004; 75: 39-48Crossref PubMed Scopus (868) Google Scholar]. In humans only one cathelicidin precursor, hCAP18, is produced, primarily in leukocytes and epithelial cells. It is cleaved to form peptide LL-37 and in some tissues a range of shorter peptides with altered properties [35Braff M.H. et al.Structure–function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities.J. Immunol. 2005; 174: 4271-4278PubMed Scopus (238) Google Scholar]. Mice also produce one cathelicidin, CRAMP, whereas in cattle and pigs the cathelicidin peptide family is highly diverse.Defensins are cationic amphipathic peptides with an approximate length of 30 amino acids and a triple-stranded β-sheet structure containing three disulfide bonds [24Ganz T. Defensins: antimicrobial peptides of innate immunity.Nat. Rev. Immunol. 2003; 3: 710-720Crossref PubMed Scopus (2465) Google Scholar]. Based on their pattern of disulfide bonding, defensins are classified into the α-, β-, and the less common θ-defensin families. In humans, α-defensins are produced in neutrophil azurophilic granules as part of their antimicrobial arsenal and by Paneth cells of the intestinal crypts, as well as by other leukocytes and epithelial cells, whereas β-defensins are produced by mucosal epithelia, skin and some leukocytes. θ-Defensins are circular peptides with anti-HIV activity that are not produced in humans and so far only found in old world monkeys [53Nguyen T.X. et al.Evolution of primate theta-defensins: a serpentine path to a sweet tooth.Peptides. 2003; 24: 1647-1654Crossref PubMed Scopus (163) Google Scholar]. Cathelicidins are cationic amphipathic peptides of diverse linear, α-helical or β-hairpin structure and are produced by proteolysis of the C-terminus of cathelin-domain-containing protein precursors [23Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity.J. Leukoc. Biol. 2004; 75: 39-48Crossref PubMed Scopus (868) Google Scholar]. In humans only one cathelicidin precursor, hCAP18, is produced, primarily in leukocytes and epithelial cells. It is cleaved to form peptide LL-37 and in some tissues a range of shorter peptides with altered properties [35Braff M.H. et al.Structure–function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities.J. Immunol. 2005; 174: 4271-4278PubMed Scopus (238) Google Scholar]. Mice also produce one cathelicidin, CRAMP, whereas in cattle and pigs the cathelicidin peptide family is highly diverse.Defensins are cationic amphipathic peptides with an approximate length of 30 amino acids and a triple-stranded β-sheet structure containing three disulfide bonds [24Ganz T. Defensins: antimicrobial peptides of innate immunity.Nat. Rev. Immunol. 2003; 3: 710-720Crossref PubMed Scopus (2465) Google Scholar]. Based on their pattern of disulfide bonding, defensins are classified into the α-, β-, and the less common θ-defensin families. In humans, α-defensins are produced in neutrophil azurophilic granules as part of their antimicrobial arsenal and by Paneth cells of the intestinal crypts, as well as by other leukocytes and epithelial cells, whereas β-defensins are produced by mucosal epithelia, skin and some leukocytes. θ-Defensins are circular peptides with anti-HIV activity that are not produced in humans and so far only found in old world monkeys [53Nguyen T.X. et al.Evolution of primate theta-defensins: a serpentine path to a sweet tooth.Peptides. 2003; 24: 1647-1654Crossref PubMed Scopus (163) Google Scholar]. Many HDPs show broad-spectrum microbicidal activity either due to interaction with and disruption of microbial membranes or translocation into bacteria to act on internal targets [26Powers J.P. Hancock R.E.W. The relationship between peptide structure and antibacterial activity.Peptides. 2003; 24: 1681-1691Crossref PubMed Scopus (779) Google Scholar]. This undoubtedly plays a key role in immune defenses within some locations, such as phagolysosomes of leukocytes and the crypts of the small intestine. However, the microbicidal activity of the peptides is highly sensitive to antagonism by divalent cations, serum and anionic macromolecules such as glycosaminoglycans [27Bowdish D.M. et al.Impact of LL-37 on anti-infective immunity.J. Leukoc. Biol. 2005; 77: 451-459Crossref PubMed Scopus (316) Google Scholar], and thus their immunomodulatory activity is probably more significant in many physiological environments. The immunomodulatory activities of HDPs include diverse effects on cell migration, survival and proliferation and the induction of many antimicrobial and immune mediators. The targets of peptide activity include leukocytes, mucosal epithelial cells, keratinocytes and vascular endothelial cells (Table 1). High sequence diversity and the multifunctional nature of HDPs provide many opportunities for the design of artificial peptides and derivatives with therapeutic applications [6Hamill P. et al.Novel anti-infectives: is host defence the answer?.Curr. Opin. Biotechnol. 2008; 19: 628-636Crossref PubMed Scopus (74) Google Scholar, 22Hancock R.E.W. Sahl H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies.Nat. Biotechnol. 2006; 24: 1551-1557Crossref PubMed Scopus (3326) Google Scholar].Table 1Immunomodulatory properties of mammalian host defense peptidesCell or tissue typePeptide production and activityReferencesHematopoietic cellsMonocytes and macrophagesLL-37 and β-defensins are monocyte chemoattractants in vitro and in vivo. LL-37 has anti-endotoxic activity, induces chemokine production, promotes IL-1β secretion, but inhibits inflammatory responses to certain TLR ligands32Mookherjee N. et al.Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37.J. Immunol. 2006; 176: 2455-2464PubMed Google Scholar, 61Soehnlein O. et al.Neutrophil secretion products pave the way for inflammatory monocytes.Blood. 2008; 112: 1461-1471Crossref PubMed Scopus (334) Google Scholar, 62Elssner A. et al.A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1β processing and release.J. Immunol. 2004; 172: 4987-4994PubMed Google ScholarNeutrophilsLL-37 and defensins are produced by neutrophils, stored within neutrophil granules and play an important microbicidal role in phagolysosomes. When released extracellularly, LL-37 acts as a neutrophil chemoattractant, inhibits neutrophil apoptosis, reduces pro-inflammatory cytokines and promotes both chemokine induction and the antimicrobial functions of neutrophils63Barlow P.G. et al.The human cationic host defense peptide LL-37 mediates contrasting effects on apoptotic pathways in different primary cells of the innate immune system.J. Leukoc. Biol. 2006; 80: 509-520Crossref PubMed Scopus (151) Google Scholar, 64Zheng Y. et al.Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human α-defensins from neutrophils.Br. J. Dermatol. 2007; 157: 1124-1131Crossref PubMed Scopus (143) Google ScholarMast cellsMast cells are important producers of LL-37 in the skin. LL-37 and β-defensins are mast cell chemoattractants and promote mast cell degranulation65Di Nardo A. et al.Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide.J. Immunol. 2003; 170: 2274-2278PubMed Google Scholar, 66Niyonsaba F. et al.Evaluation of the effects of peptide antibiotics human β-defensins-1/-2 and LL-37 on histamine release and prostaglandin D2 production from mast cells.Eur. J. Immunol. 2001; 31: 1066-1075Crossref PubMed Scopus (289) Google ScholarConventional dendritic cellsDefensins and cathelicidins are dendritic cell (DC) chemoattractants. LL-37 promotes differentiation of monocyte-derived DCs, but inhibits DC maturation and activation by TLR-ligands. β-Defensin 2 might promote DC activation as an endogenous TLR4 ligand. The adjuvant activities of defensins and cathelicidins in vivo might be mediated in part through their activity on DCs67Davidson D.J. et al.The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization.J. Immunol. 2004; 172: 1146-1156PubMed Google Scholar, 68Kandler K. et al.The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands.Int. Immunol. 2006; 18: 1729-1736Crossref PubMed Scopus (110) Google Scholar, 69Biragyn A. et al.Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2.Science. 2002; 298: 1025-1029Crossref PubMed Scopus (838) Google ScholarPlasmacytoid dendritic cellsLL-37 in complex with DNA oligonucleotides strongly induces IFNα production by plasmacytoid DCs. This activity might contribute to the pathology of psoriasis70Lande R. et al.Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.Nature. 2007; 449: 564-569Crossref PubMed Scopus (1468) Google ScholarEpithelial cellsKeratinocytesLL-37 promotes keratinocyte migration and production of IL-8, inhibits keratinocyte apoptosis, modulates responses to TLR ligands, and might have wound healing activities in the skin. Altered proteolytic processing of hCAP18 and LL-37 has been implicated in the pathology of rosacea54Carretero M. et al.In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.J. Invest. Dermatol. 2008; 128: 223-236Crossref PubMed Scopus (293) Google Scholar, 71Yamasaki K. et al.Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat. Med. 2007; 13: 975-