Antimicrobial Host Defence Peptides: Immunomodulatory Functions and Translational Prospects

  • Anne M. van der Does
  • Pieter S. Hiemstra
  • Neeloffer MookherjeeEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1117)


Cationic host defence peptides (CHDPs), also known as antimicrobial peptides, exhibit a wide range of activities contributing to immune responses and resolution of infections. CHDPs are expressed across diverse species, are generally amphipathic with less than 50 amino acids in length, and differ significantly in sequence and structure. This chapter focuses on the role of these peptides in immunity. CHDPs are known to function in both innate and adaptive immune responses. These peptides exert both pro- and anti-inflammatory properties, which are likely context dependent based on cell and tissue type, concentration of the peptides, and its interaction with other factors in the microenvironment. Furthermore, the crosstalk between CHDPs and the microbiome and how this may influence mucosal immunity is a rapidly emerging field of research. Overall, the immunomodulatory functions of CHDPs play an important role in the control of infections, regulation of inflammation, and maintaining immune homeostasis. It is thus not surprising that dysregulation of expression of CHDPs is implicated in the susceptibility, pathology, and progression of various diseases. In this chapter, we summarize the immunomodulatory functions of CHDPs, its clinical relevance, and the translational opportunities that these peptides provide for the development of new therapies.


Inflammation Immunomodulation Cathelicidin Defensin LL-37 IDR peptides 



AD is supported by an EU Marie Curie Global Fellowship (#748569). Studies in the laboratory of PSH on CHDPs are supported by grants from the Lung Foundation Netherlands, the Eurostars program, The Netherlands Organisation for Health Research and Development (ZonMw), and Galapagos NV. NM is supported by Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) for peptide research.


  1. Achtman AH, Pilat S, Law CW, Lynn DJ, Janot L, Mayer ML et al (2012) Effective adjunctive therapy by an innate defense regulatory Peptide in a preclinical model of severe malaria. Sci Transl Med 4(135):135ra64PubMedGoogle Scholar
  2. Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH (1995) FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc Natl Acad Sci U S A 92(1):195–199PubMedPubMedCentralGoogle Scholar
  3. Agerberth B, Grunewald J, Castanos-Velez E, Olsson B, Jornvall H, Wigzell H et al (1999) Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med 160(1):283–290PubMedGoogle Scholar
  4. Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L et al (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96(9):3086–3093Google Scholar
  5. Agier J, Efenberger M, Brzezinska-Blaszczyk E (2015) Cathelicidin impact on inflammatory cells. Cent Eur J Immunol 40(2):225–235PubMedPubMedCentralGoogle Scholar
  6. Ahn JK, Huang B, Bae EK, Park EJ, Hwang JW, Lee J et al (2013) The role of alpha-defensin-1 and related signal transduction mechanisms in the production of IL-6, IL-8 and MMPs in rheumatoid fibroblast-like synoviocytes. Rheumatology (Oxford) 52(8):1368–1376Google Scholar
  7. Al-Mamun A, Mily A, Sarker P, Tiash S, Navarro A, Akter M et al (2013) Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli: link to cathelicidin induction. Microbes Infect 15(13):939–950PubMedGoogle Scholar
  8. Amatngalim GD, Schrumpf JA, Henic A, Dronkers E, Verhoosel RM, Ordonez SR et al (2017) Antibacterial defense of human airway epithelial cells from chronic obstructive pulmonary disease patients induced by acute exposure to nontypeable haemophilus influenzae: modulation by cigarette smoke. J Innate Immun 9(4):359PubMedPubMedCentralGoogle Scholar
  9. Baillet A, Trocme C, Berthier S, Arlotto M, Grange L, Chenau J et al (2010) Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology (Oxford) 49(4):671–682Google Scholar
  10. Bals R, Wang X, Zasloff M, Wilson JM (1998) The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci U S A 95(16):9541–9546PubMedPubMedCentralGoogle Scholar
  11. Bals R, Weiner DJ, Moscioni AD, Meegalla RL, Wilson JM (1999) Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect Immun 67(11):6084–6089PubMedPubMedCentralGoogle Scholar
  12. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J et al (2011) Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 6(10):e25333PubMedPubMedCentralGoogle Scholar
  13. Beaumont PE, McHugh B, Gwyer Findlay E, Mackellar A, Mackenzie KJ, Gallo RL et al (2014) Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo. PLoS One 9(6):e99029PubMedPubMedCentralGoogle Scholar
  14. Beisswenger C, Kandler K, Hess C, Garn H, Felgentreff K, Wegmann M et al (2006) Allergic airway inflammation inhibits pulmonary antibacterial host defense. J Immunol 177(3):1833–1837PubMedGoogle Scholar
  15. Bergman P, Johansson L, Asp V, Plant L, Gudmundsson GH, Jonsson AB et al (2005) Neisseria gonorrhoeae downregulates expression of the human antimicrobial peptide LL-37. Cell Microbiol 7(7):1009–1017PubMedGoogle Scholar
  16. Bokarewa MI, Jin T, Tarkowski A (2003) Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis. J Rheumatol 30(8):1719–1724PubMedGoogle Scholar
  17. Bowdish DM, Davidson DJ, Scott MG, Hancock RE (2005) Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 49(5):1727–1732PubMedPubMedCentralGoogle Scholar
  18. Bracke S, Carretero M, Guerrero-Aspizua S, Desmet E, Illera N, Navarro M et al (2014) Targeted silencing of DEFB4 in a bioengineered skin-humanized mouse model for psoriasis: development of siRNA SECosome-based novel therapies. Exp Dermatol 23(3):199–201PubMedGoogle Scholar
  19. Buck CB, Day PM, Thompson CD, Lubkowski J, Lu W, Lowy DR et al (2006) Human alpha-defensins block papillomavirus infection. Proc Natl Acad Sci U S A 103(5):1516–1521PubMedPubMedCentralGoogle Scholar
  20. Bucki R, Sostarecz AG, Byfield FJ, Savage PB, Janmey PA (2007) Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum. J Antimicrob Chemother 60(3):535–545PubMedGoogle Scholar
  21. Bucki R, Leszczynska K, Namiot A, Sokolowski W (2010) Cathelicidin LL-37: a multitask antimicrobial peptide. Arch Immunol Ther Exp 58(1):15–25Google Scholar
  22. Byfield FJ, Kowalski M, Cruz K, Leszczynska K, Namiot A, Savage PB et al (2011) Cathelicidin LL-37 increases lung epithelial cell stiffness, decreases transepithelial permeability, and prevents epithelial invasion by Pseudomonas aeruginosa. J Immunol 187(12):6402–6409PubMedGoogle Scholar
  23. Chen CI, Schaller-Bals S, Paul KP, Wahn U, Bals R (2004) Beta-defensins and LL-37 in bronchoalveolar lavage fluid of patients with cystic fibrosis. J Cyst Fibros 3(1):45–50PubMedGoogle Scholar
  24. Cheng M, Ho S, Yoo JH, Tran DH, Bakirtzi K, Su B et al (2015) Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts. Clin Exp Gastroenterol 8:13–29PubMedGoogle Scholar
  25. Cherkasov A, Hilpert K, Jenssen H, Fjell CD, Waldbrook M, Mullaly SC et al (2009) Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs. ACS Chem Biol 4(1):65–74PubMedGoogle Scholar
  26. Chertov O, Michiel DF, Xu L, Wang JM, Tani K, Murphy WJ et al (1996) Identification of defensin-1, defensin-2 and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J Biol Chem 271:2935–2940PubMedGoogle Scholar
  27. Choi KY, Mookherjee N (2012) Multiple immune-modulatory functions of cathelicidin host defense peptides. Front Immunol 3:149PubMedPubMedCentralGoogle Scholar
  28. Choi KY, Chow LN, Mookherjee N (2012) Cationic host defence peptides: multifaceted role in immune modulation and inflammation. J Innate Immun 4(4):361–370PubMedGoogle Scholar
  29. Choi KY, Napper S, Mookherjee N (2014) Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation. Immunology 143(1):68–80PubMedPubMedCentralGoogle Scholar
  30. Chow LN, Choi KY, Piyadasa H, Bossert M, Uzonna J, Klonisch T et al (2014) Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis. Mol Immunol 57(2):86–92PubMedGoogle Scholar
  31. Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I et al (2006) The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 12(6):636–641PubMedGoogle Scholar
  32. Chuang CM, Monie A, Wu A, Mao CP, Hung CF (2009) Treatment with LL-37 peptide enhances antitumor effects induced by CpG oligodeoxynucleotides against ovarian cancer. Hum Gene Ther 20(4):303–313PubMedPubMedCentralGoogle Scholar
  33. Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, LaMarca HL et al (2009) The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U S A 106(10):3806–3811PubMedPubMedCentralGoogle Scholar
  34. Cowland JB, Johnsen AH, Borregaard N (1995) hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett 368(1):173–176PubMedGoogle Scholar
  35. Cullen TW, Schofield WB, Barry NA, Putnam EE, Rundell EA, Trent MS et al (2015) Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347(6218):170–175PubMedPubMedCentralGoogle Scholar
  36. Currie SM, Gwyer Findlay E, McFarlane AJ, Fitch PM, Bottcher B, Colegrave N et al (2016) Cathelicidins have direct antiviral activity against respiratory syncytial virus in vitro and protective function in vivo in mice and humans. J Immunol 196(6):2699–2710PubMedPubMedCentralGoogle Scholar
  37. Davidson DJ, Currie AJ, Reid GS, Bowdish DM, MacDonald KL, Ma RC et al (2004) The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J Immunol 172(2):1146–1156PubMedGoogle Scholar
  38. de Breij A, Riool M, Cordfunke RA, Malanovic N, de Boer L, Koning RI et al (2018) The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms. Sci Transl Med 10(423):eaan4044PubMedGoogle Scholar
  39. De Smet K, Contreras R (2005) Human antimicrobial peptides: defensins, cathelicidins and histatins. Biotechnol Lett 27(18):1337–1347PubMedGoogle Scholar
  40. De Y, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J et al (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192(7):1069–1074Google Scholar
  41. Deslouches B, Di YP (2017) Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget 8(28):46635–46651PubMedPubMedCentralGoogle Scholar
  42. Donald CD, Sun CQ, Lim SD, Macoska J, Cohen C, Amin MB et al (2003) Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas. Lab Investig 83(4):501–505PubMedGoogle Scholar
  43. Doss M, White MR, Tecle T, Hartshorn KL (2010) Human defensins and LL-37 in mucosal immunity. J Leukoc Biol 87(1):79–92PubMedGoogle Scholar
  44. Duplantier AJ, van Hoek ML (2013) The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicrobial infected wounds. Front Immunol 4:143PubMedPubMedCentralGoogle Scholar
  45. Epand RM, Vogel HJ (1999) Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta 1462(1–2):11–28PubMedGoogle Scholar
  46. Favilli F, Anzilotti C, Martinelli L, Quattroni P, De Martino S, Pratesi F et al (2009) IL-18 activity in systemic lupus erythematosus. Ann N Y Acad Sci 1173:301–309PubMedGoogle Scholar
  47. Fernandez de Caleya R, Gonzalez-Pascual B, Garcia-Olmedo F, Carbonero P (1972) Susceptibility of phytopathogenic bacteria to wheat purothionins in vitro. Appl Microbiol 23(5):998–1000PubMedGoogle Scholar
  48. Fischer N, Sechet E, Friedman R, Amiot A, Sobhani I, Nigro G et al (2016) Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge. Proc Natl Acad Sci U S A 113(21):E2993–E3001PubMedPubMedCentralGoogle Scholar
  49. Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H et al (1997) The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 272(24):15258–15263PubMedGoogle Scholar
  50. Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV et al (2007) Human -defensin-3 activates professional antigen-presenting cells via toll-like receptors 1 and 2. Proc Natl Acad Sci U S A 104(47):18631–18635PubMedPubMedCentralGoogle Scholar
  51. Ganz T (2003a) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3(9):710–720Google Scholar
  52. Ganz T (2003b) The role of antimicrobial peptides in innate immunity. Integr Comp Biol 43(2):300–304PubMedGoogle Scholar
  53. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF et al (1985) Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 76(4):1427–1435PubMedPubMedCentralGoogle Scholar
  54. Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J et al (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 3(6):583–590PubMedGoogle Scholar
  55. Gombart AF, Borregaard N, Koeffler HP (2005) Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19(9):1067–1077PubMedGoogle Scholar
  56. Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ, McDermott AM (2005) Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res 30(5):385–394PubMedPubMedCentralGoogle Scholar
  57. Gronberg A, Mahlapuu M, Stahle M, Whately-Smith C, Rollman O (2014) Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen 22(5):613–621PubMedGoogle Scholar
  58. Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R (1996) The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem 238(2):325–332Google Scholar
  59. Guo C, Rosoha E, Lowry MB, Borregaard N, Gombart AF (2013) Curcumin induces human cathelicidin antimicrobial peptide gene expression through a vitamin D receptor-independent pathway. J Nutr Biochem 24(5):754–759PubMedGoogle Scholar
  60. Han Q, Wang R, Sun C, Jin X, Liu D, Zhao X et al (2014) Human beta-defensin-1 suppresses tumor migration and invasion and is an independent predictor for survival of oral squamous cell carcinoma patients. PLoS One 9(3):e91867PubMedPubMedCentralGoogle Scholar
  61. Hanaoka Y, Yamaguchi Y, Yamamoto H, Ishii M, Nagase T, Kurihara H et al (2016) In vitro and in vivo anticancer activity of human beta-defensin-3 and its mouse homolog. Anticancer Res 36(11):5999–6004PubMedGoogle Scholar
  62. Hancock RE, Lehrer R (1998) Cationic peptides: a new source of antibiotics. Trends Biotechnol 16(2):82–88PubMedGoogle Scholar
  63. Hancock RE, Nijnik A, Philpott DJ (2012) Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10(4):243–254PubMedGoogle Scholar
  64. Hancock RE, Haney EF, Gill EE (2016) The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol 16(5):321–334PubMedGoogle Scholar
  65. Haney EF, Mansour SC, Hilchie AL, de la Fuente-Nunez C, Hancock RE (2015) High throughput screening methods for assessing antibiofilm and immunomodulatory activities of synthetic peptides. Peptides 71:276–285PubMedPubMedCentralGoogle Scholar
  66. Harder J, Bartels J, Christophers E, Schroder JM (2001) Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276(8):5707–5713PubMedGoogle Scholar
  67. Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schroder JM (2004) Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J Invest Dermatol 123(3):522–529PubMedGoogle Scholar
  68. Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF (2002) Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immun 70(2):953–963PubMedPubMedCentralGoogle Scholar
  69. Hashimoto S, Uto H, Kanmura S, Sakiyama T, Oku M, Iwashita Y et al (2012) Human neutrophil peptide-1 aggravates dextran sulfate sodium-induced colitis. Inflamm Bowel Dis 18(4):667–675PubMedGoogle Scholar
  70. Heilborn JD, Nilsson MF, Jimenez CI, Sandstedt B, Borregaard N, Tham E et al (2005) Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 114(5):713–719PubMedGoogle Scholar
  71. Hemshekhar M, Anaparti V, Mookherjee N (2016) Functions of cationic host defense peptides in immunity. Pharmaceuticals (Basel) 9(3):40Google Scholar
  72. Hensel JA, Chanda D, Kumar S, Sawant A, Grizzle WE, Siegal GP et al (2011) LL-37 as a therapeutic target for late stage prostate cancer. Prostate 71(6):659–670PubMedGoogle Scholar
  73. Herr C, Beisswenger C, Hess C, Kandler K, Suttorp N, Welte T et al (2009) Suppression of pulmonary innate host defence in smokers. Thorax 64(2):144–149PubMedGoogle Scholar
  74. Hiemstra PS (2015) Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface. Mol Immunol 68(1):28–30PubMedGoogle Scholar
  75. Hiemstra PS, Amatngalim GD, van der Does AM, Taube C (2016) Antimicrobial peptides and innate lung defenses: role in infectious and noninfectious lung diseases and therapeutic applications. Chest 149(2):545–551PubMedGoogle Scholar
  76. Hilpert K, Volkmer-Engert R, Walter T, Hancock RE (2005) High-throughput generation of small antibacterial peptides with improved activity. Nat Biotechnol 23(8):1008–1012PubMedGoogle Scholar
  77. Hilpert K, Elliott MR, Volkmer-Engert R, Henklein P, Donini O, Zhou Q et al (2006) Sequence requirements and an optimization strategy for short antimicrobial peptides. Chem Biol 13(10):1101–1107PubMedGoogle Scholar
  78. Hirsch T, Jacobsen F, Steinau HU, Steinstraesser L (2008) Host defense peptides and the new line of defence against multiresistant infections. Protein Pept Lett 15(3):238–243PubMedGoogle Scholar
  79. Hoffmann MH, Bruns H, Backdahl L, Neregard P, Niederreiter B, Herrmann M et al (2013) The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis 72(7):1239–1248PubMedGoogle Scholar
  80. Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D et al (2008) Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet 40(1):23–25PubMedGoogle Scholar
  81. Holterman DA, Diaz JI, Blackmore PF, Davis JW, Schellhammer PF, Corica A et al (2006) Overexpression of alpha-defensin is associated with bladder cancer invasiveness. Urol Oncol 24(2):97–108PubMedGoogle Scholar
  82. Hong SA, Kim KH, Lee TJ, Park ES, Kim MK, Myung SC (2017) A role of human beta defensin-1 in predicting prostatic adenocarcinoma in cases of false-negative biopsy. APMIS 125(12):1063–1069PubMedGoogle Scholar
  83. Hoppe T, Kraus D, Novak N, Probstmeier R, Frentzen M, Wenghoefer M et al (2016) Oral pathogens change proliferation properties of oral tumor cells by affecting gene expression of human defensins. Tumour Biol 37(10):13789–13798PubMedGoogle Scholar
  84. Hosoda H, Nakamura K, Hu Z, Tamura H, Reich J, Kuwahara-Arai K et al (2017) Antimicrobial cathelicidin peptide LL37 induces NET formation and suppresses the inflammatory response in a mouse septic model. Mol Med Rep 16(4):5618–5626PubMedGoogle Scholar
  85. Hou M, Zhang N, Yang J, Meng X, Yang R, Li J et al (2013) Antimicrobial peptide LL-37 and IDR-1 ameliorate MRSA pneumonia in vivo. Cell Physiol Biochem 32(3):614–623PubMedGoogle Scholar
  86. Hultmark D, Engstrom A, Bennich H, Kapur R, Boman HG (1982) Insect immunity: isolation and structure of cecropin D and four minor antibacterial components from Cecropia pupae. Eur J Biochem 127(1):207–217PubMedGoogle Scholar
  87. Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B et al (2001) Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 7(2):180–185PubMedGoogle Scholar
  88. Jia J, Zheng Y, Wang W, Shao Y, Li Z, Wang Q et al (2017) Antimicrobial peptide LL-37 promotes YB-1 expression, and the viability, migration and invasion of malignant melanoma cells. Mol Med Rep 15(1):240–248PubMedGoogle Scholar
  89. Joly S, Compton LM, Pujol C, Kurago ZB, Guthmiller JM (2009) Loss of human beta-defensin 1, 2, and 3 expression in oral squamous cell carcinoma. Oral Microbiol Immunol 24(5):353–360PubMedGoogle Scholar
  90. Jones DE, Bevins CL (1992) Paneth cells of the human small intestine express an antimicrobial peptide gene. J Biol Chem 267(32):23216–23225Google Scholar
  91. Jones DE, Bevins CL (1993) Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett 315(2):187–192PubMedGoogle Scholar
  92. Jones EA, Kananurak A, Bevins CL, Hollox EJ, Bakaletz LO (2014) Copy number variation of the beta defensin gene cluster on chromosome 8p influences the bacterial microbiota within the nasopharynx of otitis-prone children. PLoS One 9(5):e98269PubMedPubMedCentralGoogle Scholar
  93. Joo HS, Fu CI, Otto M (2016) Bacterial strategies of resistance to antimicrobial peptides. Philos Trans R Soc Lond B Biol Sci 371(1695):20150292PubMedPubMedCentralGoogle Scholar
  94. Joseph G, Tarnow L, Astrup AS, Hansen TK, Parving HH, Flyvbjerg A et al (2008) Plasma alpha-defensin is associated with cardiovascular morbidity and mortality in type 1 diabetic patients. J Clin Endocrinol Metab 93(4):1470–1475PubMedGoogle Scholar
  95. Kahlenberg JM, Kaplan MJ (2013) Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol 191(10):4895–4901PubMedGoogle Scholar
  96. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ (2013) Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol 190(3):1217–1226PubMedGoogle Scholar
  97. Kaneda Y, Yamaai T, Mizukawa N, Nagatsuka H, Yamachika E, Gunduz M et al (2009) Localization of antimicrobial peptides human beta-defensins in minor salivary glands with Sjogren’s syndrome. Eur J Oral Sci 117(5):506–510PubMedGoogle Scholar
  98. Kaplan CW, Sim JH, Shah KR, Kolesnikova-Kaplan A, Shi W, Eckert R (2011) Selective membrane disruption: mode of action of C16G2, a specifically targeted antimicrobial peptide. Antimicrob Agents Chemother 55(7):3446–3452PubMedPubMedCentralGoogle Scholar
  99. Kesting MR, Loeffelbein DJ, Hasler RJ, Wolff KD, Rittig A, Schulte M et al (2009) Expression profile of human beta-defensin 3 in oral squamous cell carcinoma. Cancer Investig 27(5):575–581Google Scholar
  100. Kesting MR, Stoeckelhuber M, Kuppek A, Hasler R, Rohleder N, Wolff KD et al (2012) Human beta-defensins and psoriasin/S100A7 expression in salivary glands: anti-oncogenic molecules for potential therapeutic approaches. BioDrugs 26(1):33–42PubMedGoogle Scholar
  101. Kienhofer D, Hahn J, Schubert I, Reinwald C, Ipseiz N, Lang SC et al (2014) No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis. PLoS One 9(12):e115474PubMedPubMedCentralGoogle Scholar
  102. Kim JE, Kim HJ, Choi JM, Lee KH, Kim TY, Cho BK et al (2010) The antimicrobial peptide human cationic antimicrobial protein-18/cathelicidin LL-37 as a putative growth factor for malignant melanoma. Br J Dermatol 163(5):959–967PubMedGoogle Scholar
  103. Kim SH, Yang IY, Kim J, Lee KY, Jang YS (2015) Antimicrobial peptide LL-37 promotes antigen-specific immune responses in mice by enhancing Th17-skewed mucosal and systemic immunities. Eur J Immunol 45(5):1402–1413PubMedGoogle Scholar
  104. Kim SH, Kim YN, Jang YS (2017) Cutting edge: LL-37-mediated formyl peptide Receptor-2 signaling in follicular dendritic cells contributes to B cell activation in Peyer’s patch germinal centers. J Immunol 198(2):629–633PubMedGoogle Scholar
  105. King AE, Fleming DC, Critchley HO, Kelly RW (2003) Differential expression of the natural antimicrobials, beta-defensins 3 and 4, in human endometrium. J Reprod Immunol 59(1):1–16PubMedGoogle Scholar
  106. Kopfnagel V, Harder J, Werfel T (2013) Expression of antimicrobial peptides in atopic dermatitis and possible immunoregulatory functions. Curr Opin Allergy Clin Immunol 13(5):531–536PubMedGoogle Scholar
  107. Kreuter A, Jaouhar M, Skrygan M, Tigges C, Stucker M, Altmeyer P et al (2011) Expression of antimicrobial peptides in different subtypes of cutaneous lupus erythematosus. J Am Acad Dermatol 65(1):125–133PubMedGoogle Scholar
  108. Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D (2005) Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 174(10):6257–6265PubMedGoogle Scholar
  109. Kuwano K, Tanaka N, Shimizu T, Kida Y (2006) Antimicrobial activity of inducible human beta defensin-2 against mycoplasma pneumoniae. Curr Microbiol 52(6):435–438PubMedGoogle Scholar
  110. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J et al (2011) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 3(73):73ra19PubMedPubMedCentralGoogle Scholar
  111. Larrick JW, Hirata M, Zhong J, Wright SC (1995) Anti-microbial activity of human CAP18 peptides. Immunotechnology 1(1):65–72PubMedGoogle Scholar
  112. Laube DM, Yim S, Ryan LK, Kisich KO, Diamond G (2006) Antimicrobial peptides in the airway. Curr Top Microbiol Immunol 306:153–182PubMedGoogle Scholar
  113. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J et al (2012) High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease. Ann Intern Med 156(2):105–114PubMedGoogle Scholar
  114. Li HN, Barlow PG, Bylund J, Mackellar A, Bjorstad A, Conlon J et al (2009) Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages. J Leukoc Biol 86(4):891–902PubMedPubMedCentralGoogle Scholar
  115. Lisanby MW, Swiecki MK, Dizon BL, Pflughoeft KJ, Koehler TM, Kearney JF (2008) Cathelicidin administration protects mice from Bacillus anthracis spore challenge. J Immunol 181(7):4989–5000PubMedPubMedCentralGoogle Scholar
  116. Luciano N, Valentini V, Calabro A, Elefante E, Vitale A, Baldini C et al (2015) One year in review 2015: Sjogren’s syndrome. Clin Exp Rheumatol 33(2):259–271PubMedGoogle Scholar
  117. Mader JS, Mookherjee N, Hancock RE, Bleackley RC (2009) The human host defense peptide LL-37 induces apoptosis in a calpain- and apoptosis-inducing factor-dependent manner involving Bax activity. Mol Cancer Res 7(5):689–702PubMedGoogle Scholar
  118. Malinovschi A, Masoero M, Bellocchia M, Ciuffreda A, Solidoro P, Mattei A et al (2014) Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients. Respir Res 15:131PubMedPubMedCentralGoogle Scholar
  119. Mallia P, Footitt J, Sotero R, Jepson A, Contoli M, Trujillo-Torralbo MB et al (2012) Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 186(11):1117–1124PubMedPubMedCentralGoogle Scholar
  120. Mangoni ML, McDermott AM, Zasloff M (2016) Antimicrobial peptides and wound healing: biological and therapeutic considerations. Exp Dermatol 25(3):167–173PubMedPubMedCentralGoogle Scholar
  121. Martineau AR, James WY, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL et al (2015) Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 3(2):120–130PubMedGoogle Scholar
  122. Meisel JS, Sfyroera G, Bartow-McKenney C, Gimblet C, Bugayev J, Horwinski J et al (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6(1):20PubMedPubMedCentralGoogle Scholar
  123. Melle C, Ernst G, Schimmel B, Bleul A, Thieme H, Kaufmann R et al (2005) Discovery and identification of alpha-defensins as low abundant, tumor-derived serum markers in colorectal cancer. Gastroenterology 129(1):66–73PubMedGoogle Scholar
  124. Merkel D, Rist W, Seither P, Weith A, Lenter MC (2005) Proteomic study of human bronchoalveolar lavage fluids from smokers with chronic obstructive pulmonary disease by combining surface-enhanced laser desorption/ionization-mass spectrometry profiling with mass spectrometric protein identification. Proteomics 5(11):2972–2980PubMedGoogle Scholar
  125. Miles K, Clarke DJ, Lu W, Sibinska Z, Beaumont PE, Davidson DJ et al (2009) Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins. J Immunol 183(3):2122–2132PubMedPubMedCentralGoogle Scholar
  126. Mily A, Rekha RS, Kamal SM, Arifuzzaman AS, Rahim Z, Khan L et al (2015) Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: a randomized controlled trial. PLoS One 10(9):e0138340PubMedPubMedCentralGoogle Scholar
  127. Miraglia E, Nylen F, Johansson K, Arner E, Cebula M, Farmand S et al (2016) Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1alpha transcription factors. Sci Rep 6:33274PubMedPubMedCentralGoogle Scholar
  128. Molhoek EM, den Hertog AL, de Vries AM, Nazmi K, Veerman EC, Hartgers FC et al (2009) Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses. Biol Chem 390(4):295–303PubMedGoogle Scholar
  129. Mookherjee N, Hancock RE (2007) Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci 64(7–8):922–933PubMedGoogle Scholar
  130. Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K et al (2006) Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol 176(4):2455–2464PubMedGoogle Scholar
  131. Mookherjee N, Hamill P, Gardy J, Blimkie D, Falsafi R, Chikatamarla A et al (2009) Systems biology evaluation of immune responses induced by human host defence peptide LL-37 in mononuclear cells. Mol BioSyst 5(5):483–496PubMedGoogle Scholar
  132. Muller CA, Markovic-Lipkovski J, Klatt T, Gamper J, Schwarz G, Beck H et al (2002) Human alpha-defensins HNPs-1, -2, and -3 in renal cell carcinoma: influences on tumor cell proliferation. Am J Pathol 160(4):1311–1324PubMedPubMedCentralGoogle Scholar
  133. Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe C, Gallo RL (2002) Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin. J Invest Dermatol 119(5):1090–1095PubMedGoogle Scholar
  134. Murakami M, Lopez-Garcia B, Braff M, Dorschner RA, Gallo RL (2004) Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J Immunol 172(5):3070–3077PubMedGoogle Scholar
  135. Nagaoka I, Tamura H, Hirata M (2006) An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2X7. J Immunol 176(5):3044–3052PubMedGoogle Scholar
  136. Nakamura T, Furunaka H, Miyata T, Tokunaga F, Muta T, Iwanaga S et al (1988) Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure. J Biol Chem 263(32):16709–16713PubMedGoogle Scholar
  137. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T et al (2017) Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 9(378):eaah4680PubMedPubMedCentralGoogle Scholar
  138. Nell MJ, Tjabringa GS, Vonk MJ, Hiemstra PS, Grote JJ (2004) Bacterial products increase expression of the human cathelicidin hCAP-18/LL-37 in cultured human sinus epithelial cells. FEMS Immunol Med Microbiol 42(2):225–231PubMedGoogle Scholar
  139. Nemeth BC, Varkonyi T, Somogyvari F, Lengyel C, Fehertemplomi K, Nyiraty S et al (2014) Relevance of alpha-defensins (HNP1-3) and defensin beta-1 in diabetes. World J Gastroenterol 20(27):9128–9137PubMedPubMedCentralGoogle Scholar
  140. Neumann A, Berends ET, Nerlich A, Molhoek EM, Gallo RL, Meerloo T et al (2014) The antimicrobial peptide LL-37 facilitates the formation of neutrophil extracellular traps. Biochem J 464(1):3–11PubMedGoogle Scholar
  141. Nijnik A, Madera L, Ma S, Waldbrook M, Elliott MR, Easton DM et al (2010) Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J Immunol 184(5):2539–2550PubMedGoogle Scholar
  142. Niyonsaba F, Madera L, Afacan N, Okumura K, Ogawa H, Hancock RE (2013) The innate defense regulator peptides IDR-HH2, IDR-1002, and IDR-1018 modulate human neutrophil functions. J Leukoc Biol 94(1):159–170PubMedGoogle Scholar
  143. Niyonsaba F, Kiatsurayanon C, Chieosilapatham P, Ogawa H (2017) Friends or foes? Host defense (antimicrobial) peptides and proteins in human skin diseases. Exp Dermatol 26(11):989–998PubMedGoogle Scholar
  144. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA et al (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414(6862):454–457PubMedGoogle Scholar
  145. Obata-Onai A, Hashimoto S, Onai N, Kurachi M, Nagai S, Shizuno K et al (2002) Comprehensive gene expression analysis of human NK cells and CD8(+) T lymphocytes. Int Immunol 14(10):1085–1098PubMedGoogle Scholar
  146. Okrent DG, Lichtenstein AK, Ganz T (1990) Direct cytotoxicity of polymorphonuclear leukocyte granule proteins to human lung-derived cells and endothelial cells. Am Rev Respir Dis 141(1):179–185PubMedGoogle Scholar
  147. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347(15):1151–1160PubMedGoogle Scholar
  148. Ostaff MJ, Stange EF, Wehkamp J (2013) Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 5(10):1465–1483PubMedPubMedCentralGoogle Scholar
  149. Pace E, Ferraro M, Minervini MI, Vitulo P, Pipitone L, Chiappara G et al (2012) Beta defensin-2 is reduced in central but not in distal airways of smoker COPD patients. PLoS One 7(3):e33601PubMedPubMedCentralGoogle Scholar
  150. Paone G, Conti V, Vestri A, Leone A, Puglisi G, Benassi F et al (2011) Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients. Dis Markers 31(2):91–100PubMedPubMedCentralGoogle Scholar
  151. Park K, Elias PM, Oda Y, Mackenzie D, Mauro T, Holleran WM et al (2011) Regulation of cathelicidin antimicrobial peptide expression by an endoplasmic reticulum (ER) stress signaling, vitamin D receptor-independent pathway. J Biol Chem 286(39):34121–34130PubMedPubMedCentralGoogle Scholar
  152. Persson LJ, Aanerud M, Hardie JA, Miodini Nilsen R, Bakke PS, Eagan TM et al (2017) Antimicrobial peptide levels are linked to airway inflammation, bacterial colonisation and exacerbations in chronic obstructive pulmonary disease. Eur Respir J 49(3):1601328PubMedGoogle Scholar
  153. Pezzulo AA, Tang XX, Hoegger MJ, Abou Alaiwa MH, Ramachandran S, Moninger TO et al (2012) Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 487(7405):109–113PubMedPubMedCentralGoogle Scholar
  154. Phan TK, Lay FT, Poon IK, Hinds MG, Kvansakul M, Hulett MD (2016) Human beta-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation. Oncotarget 7(2):2054–2069PubMedGoogle Scholar
  155. Piyadasa H, Hemshekhar M, Altieri A, Basu S, van der Does AM, Halayko AJ et al (2018a) Immunomodulatory innate defence regulator (IDR) peptide alleviates airway inflammation and hyper-responsiveness. Thorax. [Epub ahead of print]PubMedGoogle Scholar
  156. Piyadasa H, Hemshekhar M, Carlsten C, Mookherjee N (2018b) Inhaled diesel exhaust decreases the antimicrobial peptides alpha-Defensin and S100A7 in human bronchial secretions. Am J Respir Crit Care Med 197(10):1358–1361PubMedGoogle Scholar
  157. Powers JP, Hancock RE (2003) The relationship between peptide structure and antibacterial activity. Peptides 24(11):1681–1691PubMedGoogle Scholar
  158. Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C, Yip KP et al (1998) Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 152(5):1247–1258PubMedPubMedCentralGoogle Scholar
  159. Radic M (2014) Clearance of apoptotic bodies, NETs, and biofilm DNA: implications for autoimmunity. Front Immunol 5:365PubMedPubMedCentralGoogle Scholar
  160. Raqib R, Sarker P, Mily A, Alam NH, Arifuzzaman AS, Rekha RS et al (2012) Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis 12:111PubMedPubMedCentralGoogle Scholar
  161. Rehaume LM, Hancock RE (2008) Neutrophil-derived defensins as modulators of innate immune function. Crit Rev Immunol 28(3):185–200PubMedGoogle Scholar
  162. Rekha RS, Rao Muvva SS, Wan M, Raqib R, Bergman P, Brighenti S et al (2015) Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages. Autophagy 11(9):1688–1699PubMedPubMedCentralGoogle Scholar
  163. Ren SX, Cheng AS, To KF, Tong JH, Li MS, Shen J et al (2012) Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res 72(24):6512–6523PubMedPubMedCentralGoogle Scholar
  164. Rivas-Santiago B, Castaneda-Delgado JE, Rivas Santiago CE, Waldbrook M, Gonzalez-Curiel I, Leon-Contreras JC et al (2013) Ability of innate defence regulator peptides IDR-1002, IDR-HH2 and IDR-1018 to protect against Mycobacterium tuberculosis infections in animal models. PLoS One 8(3):e59119PubMedPubMedCentralGoogle Scholar
  165. Rodriguez-Jimenez FJ, Krause A, Schulz S, Forssmann WG, Conejo-Garcia JR, Schreeb R et al (2003) Distribution of new human beta-defensin genes clustered on chromosome 20 in functionally different segments of epididymis. Genomics 81(2):175–183PubMedGoogle Scholar
  166. Rohde G, Message SD, Haas JJ, Kebadze T, Parker H, Laza-Stanca V et al (2014) CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations. Clin Exp Allergy 44(7):930–939PubMedPubMedCentralGoogle Scholar
  167. Roudi R, Syn NL, Roudbary M (2017) Antimicrobial peptides as biologic and immunotherapeutic agents against cancer: a comprehensive overview. Front Immunol 8:1320PubMedPubMedCentralGoogle Scholar
  168. Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjoberg J, Amir E et al (2010) Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11(1):76–83PubMedGoogle Scholar
  169. Saraheimo M, Forsblom C, Pettersson-Fernholm K, Flyvbjerg A, Groop PH, Frystyk J (2008) Increased levels of alpha-defensin (−1, −2 and −3) in type 1 diabetic patients with nephropathy. Nephrol Dial Transplant 23(3):914–918PubMedGoogle Scholar
  170. Schauber J, Svanholm C, Termen S, Iffland K, Menzel T, Scheppach W et al (2003) Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52(5):735–741PubMedPubMedCentralGoogle Scholar
  171. Schauber J, Iffland K, Frisch S, Kudlich T, Schmausser B, Eck M et al (2004) Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells. Mol Immunol 41(9):847–854PubMedGoogle Scholar
  172. Scott MG, Vreugdenhil AC, Buurman WA, Hancock RE, Gold MR (2000) Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J Immunol 164(2):549–553PubMedGoogle Scholar
  173. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE (2002) The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 169(7):3883–3891PubMedGoogle Scholar
  174. Scott MG, Dullaghan E, Mookherjee N, Glavas N, Waldbrook M, Thompson A et al (2007) An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol 25(4):465–472PubMedGoogle Scholar
  175. Seil MN, Nagant C, Dehaye J-P, Vandenbranden M, Lensink MF (2010) Spotlight on human LL-37, an immunomodulatory peptide with promising cell-penetrating properties. Pharmaceuticals (Basel) 3(11):3435–3460Google Scholar
  176. Sharma S, Verma I, Khuller GK (2001) Therapeutic potential of human neutrophil peptide 1 against experimental tuberculosis. Antimicrob Agents Chemother 45(2):639–640PubMedPubMedCentralGoogle Scholar
  177. Sieprawska-Lupa M, Mydel P, Krawczyk K, Wojcik K, Puklo M, Lupa B et al (2004) Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob Agents Chemother 48(12):4673–4679PubMedPubMedCentralGoogle Scholar
  178. Sierra JM, Fuste E, Rabanal F, Vinuesa T, Vinas M (2017) An overview of antimicrobial peptides and the latest advances in their development. Expert Opin Biol Ther 17(6):663–676PubMedGoogle Scholar
  179. Simmaco M, Mignogna G, Barra D, Bossa F (1993) Novel antimicrobial peptides from skin secretion of the European frog Rana esculenta. FEBS Lett 324(2):159–161PubMedGoogle Scholar
  180. Simmaco M, Mignogna G, Canofeni S, Miele R, Mangoni ML, Barra D (1996) Temporins, antimicrobial peptides from the European red frog Rana temporaria. Eur J Biochem 242(3):788–792PubMedGoogle Scholar
  181. Simmaco M, Kreil G, Barra D (2009) Bombinins, antimicrobial peptides from Bombina species. Biochim Biophys Acta 1788(8):1551–1555PubMedGoogle Scholar
  182. Sorensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS et al (2001) Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97(12):3951–3959PubMedGoogle Scholar
  183. Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N (2003) Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 170(11):5583–5589PubMedGoogle Scholar
  184. Steiner H, Hultmark D, Engstrom A, Bennich H, Boman HG (1981) Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292(5820):246–248Google Scholar
  185. Steinmann J, Halldorsson S, Agerberth B, Gudmundsson GH (2009) Phenylbutyrate induces antimicrobial peptide expression. Antimicrob Agents Chemother 53(12):5127–5133PubMedPubMedCentralGoogle Scholar
  186. Steinstraesser L, Hirsch T, Schulte M, Kueckelhaus M, Jacobsen F, Mersch EA et al (2012) Innate defense regulator peptide 1018 in wound healing and wound infection. PLoS One 7(8):e39373PubMedPubMedCentralGoogle Scholar
  187. Sthoeger ZM, Bezalel S, Chapnik N, Asher I, Froy O (2009) High alpha-defensin levels in patients with systemic lupus erythematosus. Immunology 127(1):116–122PubMedPubMedCentralGoogle Scholar
  188. Stone VN, Xu P (2017) Targeted antimicrobial therapy in the microbiome era. Mol Oral Microbiol 32(6):446–454PubMedPubMedCentralGoogle Scholar
  189. Suarez-Carmona M, Hubert P, Delvenne P, Herfs M (2015) Defensins: “simple” antimicrobial peptides or broad-spectrum molecules? Cytokine Growth Factor Rev 26(3):361–370PubMedGoogle Scholar
  190. Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L et al (2015) Pancreatic beta-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota. Immunity 43(2):304–317PubMedGoogle Scholar
  191. Supanchart C, Thawanaphong S, Makeudom A, Bolscher JG, Nazmi K, Kornak U et al (2012) The antimicrobial peptide, LL-37, inhibits in vitro osteoclastogenesis. J Dent Res 91(11):1071–1077PubMedGoogle Scholar
  192. Tewary P, de la Rosa G, Sharma N, Rodriguez LG, Tarasov SG, Howard OM et al (2013) Beta-Defensin 2 and 3 promote the uptake of self or CpG DNA, enhance IFN-alpha production by human plasmacytoid dendritic cells, and promote inflammation. J Immunol 191(2):865–874PubMedPubMedCentralGoogle Scholar
  193. Tjabringa GS, Ninaber DK, Drijfhout JW, Rabe KF, Hiemstra PS (2006) Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int Arch Allergy Immunol 140(2):103–112PubMedGoogle Scholar
  194. Tomasinsig L, Zanetti M (2005) The cathelicidins – structure, function and evolution. Curr Protein Pept Sci 6(1):23–34PubMedGoogle Scholar
  195. Tongaonkar P, Golji AE, Tran P, Ouellette AJ, Selsted ME (2012) High fidelity processing and activation of the human alpha-defensin HNP1 precursor by neutrophil elastase and proteinase 3. PLoS One 7(3):e32469PubMedPubMedCentralGoogle Scholar
  196. Turner-Brannen E, Choi KY, Lippert DN, Cortens JP, Hancock RE, El-Gabalawy H et al (2011) Modulation of interleukin-1beta-induced inflammatory responses by a synthetic cationic innate defence regulator peptide, IDR-1002, in synovial fibroblasts. Arthritis Res Ther 13(4):R129PubMedPubMedCentralGoogle Scholar
  197. Uraki S, Sugimoto K, Shiraki K, Tameda M, Inagaki Y, Ogura S et al (2015) Corrigendum: human beta-defensin-3 inhibits migration of colon cancer cells via downregulation of metastasis-associated 1 family, member 2 expression. Int J Oncol 46(4):1858PubMedGoogle Scholar
  198. Valore EV, Ganz T (1992) Posttranslational processing of defensins in immature human myeloid cells. Blood 79(6):1538–1544PubMedGoogle Scholar
  199. van der Does AM, Beekhuizen H, Ravensbergen B, Vos T, Ottenhoff THM, van Dissel JT et al (2010) LL-37 directs macrophage differentiation toward macrophages with a Proinflammatory signature. J Immunol 185(3):1442–1449PubMedGoogle Scholar
  200. Van Wetering S, Mannesse-Lazeroms SPG, Van Sterkenburg MAJA, Daha MR, Dijkman JH, Hiemstra PS (1997) Effect of defensins on IL-8 synthesis in airway epithelial cells. Am J Physiol (Lung Cell Mol Physiol) 272(16):L888–LL96Google Scholar
  201. Varoga D, Paulsen FP, Kohrs S, Grohmann S, Lippross S, Mentlein R et al (2006) Expression and regulation of human beta-defensin-2 in osteoarthritic cartilage. J Pathol 209(2):166–173PubMedGoogle Scholar
  202. Varoga D, Klostermeier E, Paulsen F, Wruck C, Lippross S, Brandenburg LO et al (2009) The antimicrobial peptide HBD-2 and the toll-like receptors-2 and -4 are induced in synovial membranes in case of septic arthritis. Virchows Arch 454(6):685–694PubMedGoogle Scholar
  203. von Haussen J, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, Reimer D et al (2008) The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer 59(1):12–23Google Scholar
  204. Vordenbaumen S, Fischer-Betz R, Timm D, Sander O, Chehab G, Richter J et al (2010) Elevated levels of human beta-defensin 2 and human neutrophil peptides in systemic lupus erythematosus. Lupus 19(14):1648–1653PubMedGoogle Scholar
  205. Vragniau C, Hubner JM, Beidler P, Gil S, Saydaminova K, Lu ZZ et al (2017) Studies on the interaction of tumor-derived HD5 alpha defensins with adenoviruses and implications for oncolytic adenovirus therapy. J Virol 91(6):e02030–e02016PubMedPubMedCentralGoogle Scholar
  206. Wan M, van der Does AM, Tang X, Lindbom L, Agerberth B, Haeggstrom JZ (2014) Antimicrobial peptide LL-37 promotes bacterial phagocytosis by human macrophages. J Leukoc Biol 95(6):971–981Google Scholar
  207. Wang K, Wang JH, Baskaran H, Wang R, Jurevic R (2012) Effect of human beta-defensin-3 on head and neck cancer cell migration using micro-fabricated cell islands. Head Neck Oncol 4:41PubMedPubMedCentralGoogle Scholar
  208. Wang G, Mishra B, Epand RF, Epand RM (2014) High-quality 3D structures shine light on antibacterial, anti-biofilm and antiviral activities of human cathelicidin LL-37 and its fragments. Biochim Biophys Acta 1838(9):2160–2172PubMedPubMedCentralGoogle Scholar
  209. Wang G, Li X, Wang Z (2016) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44(D1):D1087–D1093Google Scholar
  210. Weber G, Chamorro CI, Granath F, Liljegren A, Zreika S, Saidak Z et al (2009) Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer. Breast Cancer Res: BCR 11(1):R6PubMedGoogle Scholar
  211. Welling MM, Hiemstra PS, van den Barselaar MT, Paulusma-Annema A, Nibbering PH, Pauwels EK et al (1998) Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation. J Clin Invest 102(8):1583–1590PubMedPubMedCentralGoogle Scholar
  212. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL et al (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286(5437):113–117PubMedGoogle Scholar
  213. Winter J, Kraus D, Reckenbeil J, Probstmeier R (2016) Oncogenic relevant defensins: expression pattern and proliferation characteristics of human tumor cell lines. Tumour Biol 37(6):7959–7966PubMedGoogle Scholar
  214. Woo JS, Jeong JY, Hwang YJ, Chae SW, Hwang SJ, Lee HM (2003) Expression of cathelicidin in human salivary glands. Arch Otolaryngol Head Neck Surg 129(2):211–214PubMedGoogle Scholar
  215. Wu WK, Sung JJ, To KF, Yu L, Li HT, Li ZJ et al (2010) The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J Cell Physiol 223(1):178–186PubMedGoogle Scholar
  216. Xu WD, Zhang M, Feng CC, Yang XK, Pan HF, Ye DQ (2013) IL-32 with potential insights into rheumatoid arthritis. Clin Immunol 147(2):89–94PubMedGoogle Scholar
  217. Yamaguchi Y, Nagase T, Makita R, Fukuhara S, Tomita T, Tominaga T et al (2002) Identification of multiple novel epididymis-specific beta-defensin isoforms in humans and mice. J Immunol 169(5):2516–2523PubMedGoogle Scholar
  218. Yamasaki K, Schauber J, Coda A, Lin H, Dorschner RA, Schechter NM et al (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J 20(12):2068–2080PubMedGoogle Scholar
  219. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J et al (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286(5439):525–528Google Scholar
  220. Yang D, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J et al (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utlizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192(7):1069–1074PubMedPubMedCentralGoogle Scholar
  221. Yeung AT, Gellatly SL, Hancock RE (2011) Multifunctional cationic host defence peptides and their clinical applications. Cell Mol Life Sci 68(13):2161–2176PubMedGoogle Scholar
  222. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G (2007) Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros 6(6):403–410PubMedPubMedCentralGoogle Scholar
  223. Yin J, Yu FS (2010) LL-37 via EGFR transactivation to promote high glucose-attenuated epithelial wound healing in organ-cultured corneas. Invest Ophthalmol Vis Sci 51(4):1891–1897PubMedPubMedCentralGoogle Scholar
  224. Zasloff M (1987) Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc Natl Acad Sci U S A 84(15):5449–5453PubMedPubMedCentralGoogle Scholar
  225. Zhang Z, Cherryholmes G, Shively JE (2008) Neutrophil secondary necrosis is induced by LL-37 derived from cathelicidin. J Leukoc Biol 84(3):780–788PubMedPubMedCentralGoogle Scholar
  226. Zhang Z, Cherryholmes G, Chang F, Rose DM, Schraufstatter I, Shively JE (2009) Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils. Eur J Immunol 39(11):3181–3194PubMedPubMedCentralGoogle Scholar
  227. Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, Yao S et al (2018) GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 11(3):752–762PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Anne M. van der Does
    • 1
  • Pieter S. Hiemstra
    • 1
  • Neeloffer Mookherjee
    • 2
    Email author
  1. 1.Department of PulmonologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Manitoba Centre for Proteomics and Systems Biology, Department of Internal MedicineUniversity of ManitobaWinnipegCanada

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