Molecular mechanisms of LL-37-induced receptor activation: An overview

Peptides

Volumn 85, Issue , 2016, Pages 16-26

  Verjans, Eddy Tim ^a   Zels, Sven ^a   Luyten, Walter ^a   Landuyt, Bart ^a   Schoofs, Liliane ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

G protein coupled receptor; LL 37; Membrane channel; Toll like receptor; Tyrosine kinase receptor

Indexed keywords

CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; G PROTEIN COUPLED RECEPTOR; TOLL LIKE RECEPTOR; TYROSINE KINASE RECEPTOR; ANTIMICROBIAL CATIONIC PEPTIDE; CAP18 LIPOPOLYSACCHARIDE-BINDING PROTEIN; CELL SURFACE RECEPTOR; LIGAND;

CELL MEMBRANE; HUMAN; INTRACELLULAR SIGNALING; MEMBRANE CHANNEL; MOLECULAR MECHANICS; NONHUMAN; PRIORITY JOURNAL; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; BIOSYNTHESIS; EPITHELIUM CELL; GENETICS; INFECTION; METABOLISM; PATHOLOGY; TRANSCRIPTION INITIATION;

ANTIMICROBIAL CATIONIC PEPTIDES; EPITHELIAL CELLS; HUMANS; INFECTION; LIGANDS; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; TRANSCRIPTIONAL ACTIVATION;

EID: 84986294169     PISSN: 01969781     EISSN: 18735169     Source Type: Journal    
DOI: 10.1016/j.peptides.2016.09.002     Document Type: Review

References (114)

1. [1] Wang, G., Human antimicrobial peptides and proteins. Pharmaceuticals 7:5 (2014), 545–594, 10.3390/ph7050545.
2. [2] Vandamme, D., Landuyt, B., Luyten, W., Schoofs, L., A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell. Immunol. 280:1 (2012), 22–35, 10.1016/j.cellimm.2012.11.009.
3. [3] Pinheiro da Silva, F., Machado, M.C., Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides 36:2 (2012), 308–314, 10.1016/j.peptides.2012.05.014.
4. [4] Fox, M.A., Thwaite, J.E., Ulaeto, D.O., Atkins, T.P., Atkins, H.S., Design and characterization of novel hybrid antimicrobial peptides based on cecropin A, LL-37 and magainin II. Peptides 33:2 (2012), 197–205, 10.1016/j.peptides.2012.01.013.
5. [5] Frasca, L., Lande, R., Role of defensins and cathelicidin LL37 in auto-immune and auto-inflammatory diseases. Curr. Pharm. Biotechnol. 13:10 (2012), 1882–1897, 10.2174/138920112802273155.
6. [6] Howell, M.D., Jones, J.F., Kisich, K.O., Streib, J.E., Gallo, R.L., Leung, D.Y.M., Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J. Immunol. 172:3 (2004), 1763–1767, 10.4049/jimmunol.172.3.1763.
7. [7] Yasin, B., Pang, M., Turner, J.S., Cho, Y., Dinh, N.-N., Waring, A.J., Lehrer, R.I., Wagar, E.A., Evaluation of the inactivation of infectious Herpes simplex virus by host-defense peptides. Eur. J. Clin. Microbiol. Infect. Dis. 19:3 (2000), 187–194, 10.1007/s100960050457.
8. [8] den Hertog, A.L., van Marle, J., van Veen, H.A., Van't Hof, W., Bolscher, J.G.M., Veerman, E.C.I., Nieuw Amerongen, A.V., Candidacidal effects of two antimicrobial peptides: histatin 5 causes small membrane defects, but LL-37 causes massive disruption of the cell membrane. Biochem. J. 388:Pt. 2 (2005), 689–695, 10.1042/BJ20042099.
9. [9] McGwire, B.S., Olson, L., Tack, B.F., Engman, D.M., Killing of African trypanosomes by antimicrobial peptides. J. Infect. Dis. 188:1 (2003), 146–152, 10.1086/375747.
10. [10] Dürr, U.H.N., Sudheendra, U.S., Ramamoorthy, A., LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta. 1758:9 (2006), 1408–1425, 10.1016/j.bbamem.2006.03.030.
11. [11] Koczulla, R., Von Degenfeld, G., Kupatt, C., Krötz, F., Zahler, S., Gloe, T., Issbrücker, K., Unterberger, P., Zaiou, M., Lebherz, C., Karl, A., Raake, P., Pfosser, A., Boekstegers, P., Welsch, U., Hiemstra, P.S., Vogelmeier, C., Gallo, R.L., Clauss, M., Bals, R., An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J. Clin. Invest. 111:11 (2003), 1665–1672, 10.1172/JCI200317545.
12. [12] Henzler Wildman, K.A., Lee, D.K., Ramamoorthy, A., Mechanism of lipid Bilayer disruption by the human antimicrobial peptide, LL-37. Biochemistry 42:21 (2003), 6545–6558, 10.1021/bi0273563.
13. [13] Chung, M.-C., Dean, S.N., van Hoek, M.L., Acyl carrier protein is a bacterial cytoplasmic target of cationic antimicrobial peptide LL-37. Biochem. J. 470:2 (2015), 243–253, 10.1042/bj20150432.
14. [14] Liu, W., Dong, S.L., Xu, F., Wang, X.Q., Withers, T.R., Yu, H.D., Wang, X., Effect of intracellular expression of antimicrobial peptide LL-37 on growth of Escherichia coli strain TOP10 under aerobic and anaerobic conditions. Antimicrob. Agents Chemother. 57:10 (2013), 4707–4716, 10.1128/aac.00825-13.
15. [15] Yang, De, Chen, Q., Schmidt, A.P., Anderson, G.M., Wang, J.M., Wooters, J., Oppenheim, J.J., Chertov, O., 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 (2000), 1069–1074, 10.1084/jem.192.7.1069.
16. [16] Seil, M., Nagant, C., Dehaye, J.P., Vandenbranden, M., Lensink, M.F., Spotlight on human LL-37, an immunomodulatory peptide with promising cell-penetrating properties. Pharmaceuticals 3:11 (2010), 3435–3460, 10.3390/ph3113435.
17. [17] Nijnik, A., Pistolic, J., Wyatt, A., Tam, S., Hancock, R.E.W., Human cathelicidin peptide LL-37 modulates the effects of IFN-gamma on APCs. J. Immunol. 183:9 (2009), 5788–5798, 10.4049/jimmunol.0901491.
18. [18] Reinholz, M., Ruzicka, T., Schauber, J., Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann. Dermatol. 24:2 (2012), 126–135, 10.5021/ad2012.24.2.126.
19. [19] Barlow, P.G., Li, Y., Wilkinson, T.S., Bowdish, D.M.E., Lau, Y.E., Cosseau, C., Haslett, C., Simpson, a J., Hancock, R.E.W., Davidson, D.J., 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. 80:3 (2006), 509–520, 10.1189/jlb.1005560.
20. [20] Barlow, P.G., Beaumont, P.E., Cosseau, C., Mackellar, A., Wilkinson, T.S., Hancock, R.E.W., Haslett, C., Govan, J.R.W., Simpson, A.J., Davidson, D.J., The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am. J. Respir. Cell Mol. Biol. 43:6 (2010), 692–702, 10.1165/rcmb.2009-0250oc.
21. [21] Heilborn, J.D., Nilsson, M.F., Kratz, G., Weber, G., Sørensen, O., Borregaard, N., Ståhle-bäckdahl, M., The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120:3 (2003), 379–389, 10.1046/j.1523-1747.2003.12069.x.
22. [22] Ramos, R., Silva, J.P., Rodrigues, A.C., Costa, R., Guardão, L., Schmitt, F., Soares, R., Vilanova, M., Comingues, L., Gama, M., Wound healing activity of the human antimicrobial peptide LL37. Peptides 32:7 (2011), 1469–1476, 10.1016/j.peptides.2011.06.005.
23. [23] Otte, J.-M., Zdebik, A.-E., Brand, S., Chromik, A.M., Strauss, S., Schmitz, F., Steinstraesser, L., Schmidt, W.E., Effect of the cathelicidin LL-37 on intestinal epithelial barrier integrity. Regul. Pept. 156:1–3 (2009), 104–117, 10.1016/j.regpep.2009.03.009.
24. [24] Kuroda, K., Okumura, K., Isogai, H., Isogai, E., The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. Front. Oncol. 5:144 (2015), 1–10, 10.3389/fonc.2015.00144.
25. [25] Chen, C.I., Schaller-Bals, S., Paul, K.P., Wahn, U., Bals, R., Beta-defensins and LL-37 in bronchoalveolar lavage fluid of patients with cystic fibrosis. J. Cyst. Fibros. 3:1 (2004), 45–50, 10.1016/j.jcf.2003.12.008.
26. [26] Xhindoli, D., Pacor, S., Benincasa, M., Scocchi, M., Gennaro, R., Tossi, A., The human cathelicidin LL-37 – a pore-forming antibacterial peptide and host-cell modulator. Biochim. Biophys. Acta Biomembr. 1858:3 (2015), 546–566, 10.1016/j.bbamem.2015.11.003.
27. [27] Hoang-Yen Tran, D., Hoang-Ngoc Tran, D., Mattai, S.A., Sallam, T., Ortiz, C., Lee, E.C., Robbins, L., Ho, S., Lee, J.E., Fisseha, E., Shieh, C., Sideri, A., Shih, D.Q., Fleshner, P., McGovern, D.P.B., Vu, M., Hing, T.C., Bakirtzi, K., Cheng, M., Su, B., Law, I., Karagiannides, I., Targan, S.R., Gallo, R.L., Li, Z., Koon, H.W., Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor. Int. J. Obes., 2016, 10.1038/ijo.2016.90 (Epub ahead of print).
28. [28] Gallo, R.L., Sounding the alarm: multiple functions of host defense peptides. J. Invest. Dermatol. 128:1 (2008), 5–6, 10.1038/sj.jid.5701073.
29. [29] Tjabringa, G.S., Aarbiou, J., Ninaber, D.K., Drijfhout, J.W., Sørensen, O.E., Borregaard, N., Rabe, K.F., Hiemstra, P.S., The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. J. Immunol. 171:12 (2003), 6690–6696, 10.4049/jimmunol.171.12.6690.
30. [30] Wu, W., Kim, C.H., Liu, R., Kucia, M., Marlicz, W., Greco, N., Ratajczak, J., Laughlin, M.J., Ratajczak, M.Z., The bone marrow-expressed antimicrobial cationic peptide LL-37 enhances the responsiveness of hematopoietic stem progenitor cells to an SDF-1 gradient and accelerates their engraftment after transplantation. Leukemia 26:4 (2012), 736–745, 10.1038/leu.2011.252.
31. [31] Mookherjee, N., Lippert, D.N.D., Hamill, P., Falsafi, R., Nijnik, A., Kindrachuk, J., Pistolic, J., Gardy, J., Miri, P., Naseer, M., Foster, L.J., Hancock, R.E.W., Intracellular receptor for human host defense peptide LL-37 in monocytes. J. Immunol. 183:4 (2009), 2688–2696, 10.4049/jimmunol.0802586.
32. [32] Zhang, X., Bajic, G., Andersen, G.R., Christiansen, S.H., Vorup-Jensen, T., The cationic peptide LL-37 binds Mac-1 (CD11b/CD18) with a low dissociation rate and promotes phagocytosis. Biochim. Biophys. Acta 1864:5 (2016), 471–478, 10.1016/j.bbapap.2016.02.013.
33. [33] Gambade, A., Zreika, S., Guéguinou, M., Chourpa, I., Fromont, G., Bouchet, A.M., Burlaud-gaillard, J., Potier-cartereau, M., Roger, S., Aucagne, V., Chevalier, S., Vandier, C., Goupille, C., Weber, G., Activation of TRPV2 and BKCa channels by the LL-3 enantiomers stimulates calcium entry and migration of cancer cells. Oncotarget 7:17 (2016), 2385–23800, 10.18632/oncotarget.8122.
34. [34] Cattaneo, F., Parisi, M., Ammendola, R., Distinct signaling cascades elicited by different formyl peptide receptor 2 (FPR2) agonists. Int. J. Mol. Sci. 14:4 (2013), 7193–7230, 10.3390/ijms14047193.
35. [35] Li, Y., Cai, L., Wang, H., Wu, P., Gu, W., Chen, Y., Hao, H., Tang, K., Yi, P., Liu, M., Miao, S., Ye, D., Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2. Oncogene 30:36 (2011), 3887–3899, 10.1038/onc.2011.112.
36. [36] Nagaoka, I., Tamura, H., Hirata, M., 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 (2006), 3044–3052, 10.4049/jimmunol.176.5.3044.
37. [37] Wan, M., Godson, C., Guiry, P.J., Agerberth, B., Haeggström, J.Z., Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1. FASEB J. 25:5 (2011), 1697–1705, 10.1096/fj.10-175687.
38. [38] Sun, J., Dahlén, B., Agerberth, B., Haeggström, J.Z., The antimicrobial peptide LL-37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils – implications for asthma. Allergy Eur. J. Allergy Clin. Immunol. 68:3 (2013), 304–311, 10.1111/all.12087.
39. [39] Tripathi, S., Wang, G., White, M., Rynkiewicz, M., Seaton, B., Hartshorn, K., Identifying the critical domain of LL-37 involved in mediating neutrophil activation in the presence of influenza virus: functional and structural analysis. PLoS One 10:8 (2015), 1–15, 10.1371/journal.pone.0133454.
40. [40] Gordon, Y.J., Huang, L.C., Romanowski, E.G., Yates, K.A., Proske, R.J., McDermotte, A.M., Human cathlecidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr. Eye Res. 30:5 (2005), 385–394, 10.1080/02713680590934111.
41. [41] Iaccio, A., Cattaneo, F., Mauro, M., Ammendola, R., FPRL1-mediated induction of superoxide in LL-37-stimulated IMR90 human fibroblast. Arch. Biochem. Biophys. 481:1 (2009), 94–100, 10.1016/j.abb.2008.10.026.
42. [42] Byfield, F.J., Kowalski, M., Cruz, K., Leszczyńska, K., Namiot, A., Savage, P.B., Bucki, R., Janmey, P.a., Cathelicidin LL-37 increases lung epithelial cell stiffness, decreases transepithelial permeability, and prevents epithelial invasion by Pseudomonas aeruginosa. J. Immunol. 187:12 (2011), 6402–6409, 10.4049/jimmunol.1102185.
43. [43] Addison, C.L., Daniel, T.O., Burdick, M.D., Liu, H., Ehlert, J.E., Xue, Y.Y., Buechi, L., Walz, A., Richmond, A., Strieter, R.M., The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J. Immunol. 165:9 (2000), 5269–5277, 10.4049/jimmunol.165.9.5269.
44. [44] Zhang, Z., Cherryholmes, G., Chang, F., Rose, D.M., Schraufstatter, I., Shively, J.E., Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils. Eur. J. Immunol. 39:11 (2009), 3181–3194, 10.1002/eji.200939496.
45. [45] Subramanian, H., Gupta, K., Guo, Q., Price, R., Ali, H., Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. J. Biol. Chem. 286:52 (2011), 44739–44749, 10.1074/jbc.m111.277152.
46. [46] Wu, H., Zeng, M., Cho, E.Y.P., Jiang, W., Sha, O., The origin, expression, function and future research focus of a G protein-coupled receptor, mas-related gene X2 (MrgX2). Prog. Histochem. Cytochem. 50:1–2 (2015), 11–17, 10.1016/j.proghi.2015.06.001.
47. [47] Brandenburg, L.O., Jansen, S., Wruck, C.J., Lucius, R., Pufe, T., Antimicrobial peptide rCRAMP induced glial cell activation through P2Y receptor signalling pathways. Mol. Immunol. 47:10 (2010), 1905–1913, 10.1016/j.molimm.2010.03.012.
48. [48] Solinski, H.J., Gudermann, T., Breit, A., Pharmacology and signaling of MAS-Related G protein-coupled receptors. Pharmacol. Rev. 66:3 (2014), 570–597, 10.1124/pr.113.008425.
49. [49] Pike, L.J., Lipid rafts: bringing order to chaos. J. Lipid Res. 44:4 (2003), 655–667, 10.1194/jlr.r200021-jlr200.
50. [50] Lemmon, M.A., Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell 141:7 (2010), 1117–1134, 10.1016/j.cell.2010.06.011.
51. [51] Wieduwilt, M.J., Moasser, M.M., The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci. 65:10 (2008), 1566–1584, 10.1007/s00018-008-7440-8.
52. [52] Yin, J., Yu, F.S.X., Ll-37 via EGFR transactivation to promote high glucose-attenuated epithelial wound healing in organ-cultured corneas. Invest. Ophthalmol. Vis. Sci. 51:4 (2010), 1891–1897, 10.1167/iovs.09-3904.
53. [53] Shaykhiev, R., Beisswenger, C., Kändler, K., Senske, J., Püchner, A., Damm, T., Behr, J., Bals, R., Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am. J. Physiol. Lung Cell. Mol. Physiol. 289:5 (2005), L842–L848, 10.1152/ajplung.00286.2004.
54. [54] Zhang, Y., Jiang, Y., Sun, C., Wang, Q., Yang, Z., Pan, X., Zhu, M., Xiao, W., The human cathelicidin LL-37 enhances airway mucus production in chronic obstructive pulmonary disease. Biochem. Biophys. Res. Commun. 443:1 (2014), 103–109, 10.1016/j.bbrc.2013.11.074.
55. [55] Yang, Y.H., Wu, W.K., Tai, E.K., Wong, H.P., Lam, E.K., So, W.H., Shin, V.Y., Cho, C.H., The cationic host defense peptide rCRAMP promotes gastric ulcer healing in rats. J. Pharmacol. Exp. Ther. 318:2 (2006), 547–554, 10.1124/jpet.106.102467.
56. [56] Tokumaru, S., Sayama, K., Shirakata, Y., Komatsuzawa, H., Ouhara, K., Hanakawa, Y., Yahata, Y., Dai, X., Tohyama, M., Nagai, H., Yang, L., Higashiyama, S., Yoshimura, A., Sugai, M., Hashimoto, K., Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J. Immunol. 175:7 (2005), 4662–4668, 10.4049/jimmunol.175.7.4662.
57. [57] Carretero, M., Escámez, M.J., García, M., Duarte, B., Holguín, A., Retamosa, L., Jorcano, J.L., Río, M.D., Larcher, F., In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128:1 (2008), 223–236, 10.1038/sj.jid.5701043.
58. [58] Kajiya, M., Shiba, H., Komatsuzawa, H., Ouhara, K., Fujita, T., Takeda, K., Uchida, Y., Mizuno, N., Kawaguchi, H., Kurihara, H., The antimicrobial peptide LL37 induces the migration of human pulp cells: a possible adjunct for regenerative endodontics. J. Endod. 36:6 (2010), 1009–1013, 10.1016/j.joen.2010.02.028.
59. [59] Shaykhiev, R., Sierigk, J., Herr, C., Krasteva, G., Kummer, W., Bals, R., The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS. FASEB J. 24:12 (2010), 4756–4766, 10.1096/fj.09-151332.
60. [60] von Haussen, J., Koczulla, R., Shaykhiev, R., Herr, C., Pinkenburg, O., Reimer, D., Wiewrodt, R., Biesterfeld, S., Aigner, A., Czubayko, F., Bals, R., The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer 59:1 (2008), 12–23, 10.1016/j.lungcan.2007.07.014.
61. [61] Girnita, A., Zheng, H., Grönberg, A., Girnita, L., Ståhle, M., Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene 31:3 (2012), 352–365, 10.1038/onc.2011.239.
62. [62] Weber, G., Chamorro, C.I., Granath, F., Liljegren, A., Zreika, S., Saidak, Z., Sandstedt, B., Rotstein, S., Mentaverri, R., Sánchez, F., Pivarcsi, A., Ståhle, M., Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer. Breast Cancer Res., 11(1), 2009, R6, 10.1186/bcr2221.
63. [63] Luttrell, D.K., Luttrell, L.M., Not so strange bedfellows: g-protein-coupled receptors and Src family kinases. Oncogene 23:48 (2004), 7969–7978, 10.1038/sj.onc.1208162.
64. [64] Gschwind, A., Zwick, E., Prenzel, N., Leserer, M., Ullrich, A., Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 20:13 (2001), 1594–1600, 10.1038/sj.onc.1204192.
65. [65] Huang, L.C., Petkova, T.D., Reins, R.Y., Proske, R.J., McDermott, A.M., Multifunctional roles of human cathelicidin (LL-37) at the ocular surface. Invest. Ophthalmol. Vis. Sci. 47:6 (2006), 2369–2380, 10.1167/iovs.05-1649.
66. [66] Braff, M.H., Hawkins, M.A., Di Nardo, A., Lopez-Garcia, B., Howell, M.D., Wong, C., Lin, K., Streib, J.E., Dorschner, R., Leung, D.Y., Gallo, R.L., Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J. Immunol. 174:7 (2005), 4271–4278, 10.4049/jimmunol.174.7.4271.
67. [67] Wu, W.K., Wang, G., Coffelt, S.B., Betancourt, A.M., Lee, C.W., Wu, K., Yu, J., Sung, J.J., Cho, C.H., Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int. J. Cancer 127:8 (2011), 1741–1747, 10.1002/ijc.25489.
68. [68] Frei, A.P., Jeon, O.-Y., Kilcher, S., Moest, H., Henning, L.M., Jost, C., Plückthun, A., Mercer, J., Aebersold, R., Carreira, E.M., Wollscheid, B., Direct identification of ligand-receptor interactions on living cells and tissues. Nat. Biotechnol. 30:10 (2012), 997–1001, 10.1038/nbt.2354.
69. [69] Volonté, C., Apolloni, S., Skaper, S.D., Burnstock, G., ×, P.2, P2X7 receptors: channels, pores and more. CNS Neurol. Disord. Drug Targets 11:6 (2012), 705–721, 10.2174/187152712803581137.
70. [70] Wiley, R., Sluyter, B.J., Gu, L., The human P2X7 receptor and its role in innate immunity. Tissue Antigens 78:5 (2011), 321–332, 10.1111/j.1399-0039.2011.01780.x.
71. [71] Michel, A.D., Fonfria, E., Agonist potency at P2X7 receptors is modulated by structurally diverse lipids. Br. J. Pharmacol. 152:4 (2007), 523–537, 10.1038/sj.bjp.0707417.
72. [72] Skaper, S.D., Debetto, P., Giusti, P., The P2X7eceptors in neurological and cardiovascular disorders, cardiovasc. Psychiatry Neurol., 2009, 2009, 861324, 10.1155/2009/861324.
73. [73] Bartlett, R., Stokes, L., Sluyter, R., The P2X7eceptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol. Rev. 66:3 (2014), 638–675, 10.1124/pr.113.008003.
74. [74] Elssner, A., Duncan, M., Gavrilin, M., Wewers, M.D., A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1β processing and release. J. Immunol. 172:8 (2004), 4987–4994, 10.4049/jimmunol.172.8.4987.
75. [75] Montreekachon, P., Chotjumlong, P., Bolscher, J.G.M., Nazmi, K., Reutrakul, V., Krisanaprakornkit, S., Involvement of P2X7 purinergic receptor and MEK1/2 in interleukin-8 up-regulation by LL-37 in human gingival fibroblasts. J. Periodontal Res. 46:3 (2011), 327–337, 10.1111/j.1600-0765.2011.01346.x.
76. [76] Tomasinsig, L., Pizzirani, C., Skerlavaj, B., Pellegatti, P., Gulinelli, S., Tossi, A., Di Virgilio, F., Zanetti, M., The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner. J. Biol. Chem. 283:5 (2008), 30471–30481, 10.1074/jbc.M802185200.
77. [77] Tang, X., Basavarajappa, D., Haeggström, J.Z., Wan, M., P2X7 receptor regulates internalization of antimicrobial peptide LL-37 by human macrophages that promotes intracellular pathogen clearance. J. Immunol. 195:3 (2015), 1191–1201, 10.4049/jimmunol.1402845.
78. [78] Rekha, R.S., Rao Muvva, S.S., Wan, M., Raqib, R., Bergman, P., Brighenti, S., Gudmundsson, G.H., Agerberth, B., Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of mycobacterium tuberculosis in human macrophages. Autophagy 11:9 (2015), 1688–1699, 10.1080/15548627.2015.1075110.
79. [79] Wan, M., Soehnlein, O., Tang, X., Van Der Does, A.M., Smedler, E., Uhlén, P., Lindbom, L., Agerberth, B., Haeggström, J.Z., Cathelicidin LL-37 induces time-resolved release of LTB4 and TXA2 by human macrophages and triggers eicosanoid generation in vivo. FASEB J. 28:8 (2014), 3456–3467, 10.1096/fj.14-251306.
80. [80] Sainz, B., Alcala, S., Garcia, E., Sanchez-Ripoll, Y., Azevedo, M.M., Cioffi, M., Tatari, M., Miranda-Lorenzo, I., Hidalgo, M., Gomez-Lopez, G., Canamero, M., Erkan, M., Kleeff, J., Garcia-Silva, S., Sancho, P., Hermann, P.C., Heeschen, C., Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut 64:12 (2015), 1921–1935, 10.1136/gutjnl-2014-308935.
81. [81] Piktel, E., Niemirowicz, K., Wnorowska, U., Wątek, M., Wollny, T., Głuszek, K., Góźdź, S., Levental, I., Bucki, R., The role of cathelicidin LL-37 in cancer development. Arch. Immunol. Ther. Exp. 64:1 (2015), 33–46, 10.1007/s00005-015-0359-5.
82. [82] Pochet, S., Tandel, S., Querriére, S., Tre-Hardy, M., Garcia-Marcos, M., De Lorenzi, M., Vandenbranden, M., Marino, A., Devleeschouwer, M., Dehaye, J.-P., Modulation by LL-37 of the responses of salivary glands to purinergic agonists. Mol. Pharmacol. 69:6 (2006), 2037–2046, 10.1124/mol.105.021444.
83. [83] Seil, M., Kabré, E., Nagant, C., Vandenbranden, M., Fontanils, U., Marino, A., Pochet, S., Dehaye, J.-P., Regulation by CRAMP of the responses of murine peritoneal macrophages to extracellular ATP. Biochim. Biophys. Acta. 1798:3 (2010), 569–578, 10.1016/j.bbamem.2009.11.002.
84. [84] Young, M.T., Pelegrin, P., Surprenant, A., Amino acid residues in the P2X7 receptor that mediate differential sensitivity to ATP and BzATP. Mol. Pharmacol. 71:1 (2007), 92–100, 10.1124/mol.106.030163.
85. [85] Wewers, M.D., Sarkar, A., P2X7 receptor and macrophage function. Purinergic Signal. 5:2 (2009), 189–195, 10.1007/s11302-009-9131-9.
86. [86] Hu, Z., Murakami, T., Suzuki, K., Tamura, H., Kuwahara-Arai, K., Iba, T., Nagaoka, I., Antimicrobial cathelicidin peptide LL-37 inhibits the LPS/ATP-induced pyroptosis of macrophages by dual mechanism. PLoS One., 9(1), 2014, 10.1371/journal.pone.0085765.
87. [87] Murgia, M., Hanau, S., Pizzo, P., Rippa, M., Di Virgilio, F., Oxidized, A.T.P., An irreversible inhitibor of the macrophage purinergic P2Z receptor. J. Biol. Chem. 268 (1993), 8199–8203.
88. [88] Beutler, B.A., Review article TLRs and innate immunity. Blood 113:7 (2009), 1399–1407, 10.1182/blood-2008-07-019307.
89. [89] Blasius, A.L., Beutler, B., Intracellular toll-like receptors. Immunity 32:3 (2010), 305–315, 10.1016/j.immuni.2010.03.012.
90. [90] Into, T., Inomata, M., Shibata, K., Murakami, Y., Effect of the antimicrobial peptide LL-37 on toll-like receptors 2-, 3- and 4-triggered expression of IL-6, IL-8 and CXCL10 in human gingival fibroblasts. Cell. Immunol. 264:1 (2010), 104–109, 10.1016/j.cellimm.2010.05.005.
91. [91] Mookherjee, N., Brown, K.L., Bowdish, D.M.E., Doria, S., Falsafi, R., Hokamp, K., Roche, F.M., Mu, R., Doho, G.H., Pistolic, J., Powers, J.-P., Bryan, J., Brinkman, F.S., Hancock, R.E., Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 176:4 (2006), 2455–2464, 10.4049/jimmunol.176.4.2455.
92. [92] Di Nardo, A., Braff, M.H., Taylor, K.R., Na, C., Granstein, R.D., McInturff, J.E., Krutzik, S., Modlin, R.L., Gallo, R.L., Cathelicidin antimicrobial peptides block dendritic cell TLR4 activation and allergic contact sensitization. J. Immunol. 178:3 (2007), 1829–1834, 10.4049/jimmunol.178.3.1829.
93. [93] Kahlenberg, J.M., Kaplan, M.J., Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J. Immunol. 191:10 (2013), 4895–4901, 10.4049/jimmunol.1302005.
94. [94] Ganguly, D., Chamilos, G., Lande, R., Gregorio, J., Meller, S., Facchinetti, V., Homey, B., Barrat, F.J., Zal, T., Gilliet, M., Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J. Exp. Med. 206:9 (2009), 1983–1994, 10.1084/jem.20090480.
95. [95] Gilliet, M., Lande, R., Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr. Opin. Immunol. 20:4 (2008), 401–407, 10.1016/j.coi.2008.06.008.
96. [96] Filewod, N.C., Pistolic, J., Hancock, R.E., Low concentrations of LL-37 alter IL-8 production by keratinocytes and bronchial epithelial cells in response to proinflammatory stimuli. FEMS Immunol. Med. Microbiol. 56:3 (2009), 233–240, 10.1111/j.1574-695x.2009.00571.x.
97. [97] Singh, D., Qi, R., Jordan, J.L., San Mateo, L., Kao, C.C., The human antimicrobial peptide LL-37, but not the mouse ortholog, mCRAMP, can stimulate signaling by poly(I:C) through a FPRL1-dependent pathway. J. Biol. Chem. 288:12 (2013), 8258–8268, 10.1074/jbc.m112.440883.
98. [98] Sandgren, S., Wittrup, A., Cheng, F., Jönsson, M., Eklund, E., Busch, S., Belting, M., The human antimicrobial peptide LL-37 transfers extracellular DNA plasmid to the nuclear compartment of mammalian cells via lipid rafts and proteoglycan-dependent endocytosis. J. Biol. Chem. 279:17 (2004), 17951–17956, 10.1074/jbc.m311440200.
99. [99] Singh, D., Vaughan, R., Kao, C.C., LL-37 peptide enhancement of signal transduction by toll-like receptor 3 is regulated by pH identification of a peptide antagonist of LL-37. J. Biol. Chem. 289:40 (2014), 27614–27624, 10.1074/jbc.m114.582973.
100. [100] Oren, Z., Lerman, J.C., Gudmundsson, G.H., Agerberth, B., Shai, Y., Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem. J. 341:Pt. 3 (1999), 501–513, 10.1042/bj3410501.
101. [101] Sood, R., Domanov, Y., Pietiäinen, M., Kontinen, V.P., Kinnunen, P.K.J., Binding of LL-37 to model biomembranes: insight into target vs host cell recognition. Biochim. Biophys. Acta 1778:4 (2008), 983–996, 10.1016/j.bbamem.2007.11.016.
102. [102] Zhang, X., Oglecka, K., Sandgren, S., Belting, M., Esbjörner, E.K., Nordén, B., Gräslund, A., Dual functions of the human antimicrobial peptide LL-37- Target membrane perturbation and host cell cargo delivery. Biochim. Biophys. Acta Biomembr. 1798:12 (2010), 2201–2208, 10.1016/j.bbam.2009.12.011.
103. [103] Rao, N.M., Differential susceptibility of phosphatidylcholine small unilamellar vesicles to phospholipases A2, C and D in the presence of membrane active peptides. Biochem. Biophys. Res. Commun. 182:2 (1992), 682–688, 10.1016/0006-291x(92)91786-p.
104. [104] Bucki, R., Pastore, J.J., Randhawa, P., Vegners, R., Weiner, D.J., Janmey, P.A., Antibacterial activities of rhodamine B-conjugated gelsolin-derived peptides compared to those of the antimicrobial peptides cathelicidin LL37, magainin II and melittin. Antimicrob. Agents Chemother. 48:5 (2004), 1526–1533, 10.1128/aac.48.5.1526-1533.2004.
105. [105] Ding, B., Soblosky, L., Nguyen, K., Geng, J., Yu, X., Ramamoorthy, A., Chen, Z., Physiologically-relevant modes of membrane interactions by the human antimicrobial peptide, LL-37, revealed by SFG experiments. Sci. Rep. 3:1854 (2013), 1–8, 10.1038/srep01854.
106. [106] Wang, G., Mishra, B., Epand, R.F., Epand, R.M., High-quality 3D structures shine light on antibacterial, anti-biofilm and antiviral activities of human cathelicidin LL-37 and its fragments. Biochim. Biophys. Acta Biomembr. 1838:9 (2014), 2160–2172, 10.1016/j.bbamem.2014.01.016.
107. [107] Xhindoli, D., Pacor, S., Guida, F., Antcheva, N., Tossi, A., Native oligomerization determines the mode of action and biological activities of human cathelicidin LL-37. Biochem. J. 457:2 (2014), 263–275, 10.1042/bj20131048.
108. [108] Sevcsik, E., Pabst, G., Richter, W., Danner, S., Amenitsch, H., Lohner, K., Interaction of LL-37 with model membrane systems of different complexity: influence of the lipid matrix. Biophys. J. 94:12 (2008), 4688–4699, 10.1529/biophysj.107123620.
109. [109] Hoskin, D.W., Ramamoorthy, A., Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta 1778:2 (2008), 357–375, 10.1016/j.bbamem.2007.11.008.
110. [110] Suzuki, K., Murakami, T., Hu, Z., Tamura, H., Kuwahara-Arai, K., Iba, T., Nagaoka, I., Human host defense cathelicidin peptide LL-37 enhances the lipopolysaccharide uptake by liver sinusoidal endothelial cells without cell activation. J. Immunol. 196:3 (2016), 1338–1347, 10.1049/jimmunol.1403203.
111. [111] Gudmundsson, G.H., Agerberth, B., Odeberg, J., Bergman, T., Olsson, B., Salcedo, R., The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur. J. Biochem. 238:2 (1996), 325–332, 10.1111/j.1432-1033.1996.0325z.x.
112. [112] Ren, S.X., Shen, J., Cheng, A.S., Lu, L., Chan, R.L., Li, Z.J., Wang, X.J., Wong, C.C., Zhang, F.L., Ng, S.S., Chan, F.L., Chan, F.K., Yu, J., Sung, J.J., Wu, W.K., Cho, C.H., FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS One 8:5 (2013), 1–9, 10.1371/journal.pone.0063641.
113. [113] Park, H.J., Cho, D.H., Kim, H.J., Lee, J.Y., Cho, B.K., Bang, S.I., Song, S.Y., Yamasaki, K., Di Nardo, A., Gallo, R.L., Collagen synthesis is suppressed in dermal fibroblasts by the human antimicrobial peptide LL-37. J. Invest. Dermatol. 129:4 (2009), 843–850, 10.1038/jid.2008.320.
114. [114] Lau, Y.E., Rozek, A., Scott, M.G., Goosney, D.L., Davidson, D.J., Hancock, R.E.W., Interaction and cellular localization of the human host defense peptide LL-37 with interaction and cellular localization of the human host defense peptide LL-37 with lung epithelial cells. Infect. Immun. 73:1 (2005), 583–591, 10.1128/IAI.73.1.583-591.2005.