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Roles of cathelicidins in inflammation and bone loss

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Abstract

Body surface tissues, such as the oral cavity, contact directly with the external environment and are continuously exposed to microbial insults. Cathelicidins are a family of antimicrobial peptides that are found in mammalian species. Humans and mice have only one cathelicidin. Cathelicidins are expressed in a variety of surface tissues. In addition, they are abundantly expressed in bone and bone marrow. Infectious stimuli upregulate the expression of cathelicidins, which play sentinel roles in allowing the tissues to fight against microbial challenges. Cathelicidins disrupt membranes of microorganisms and kill them. They also neutralize microbe-derived pathogens, such as lipopolysaccharide (LPS) and flagellin. Besides their antimicrobial functions, cathelicidins can also control actions of host cells, such as chemotaxis, proliferation, and cytokine production, through binding to the receptors expressed on them. LPS and flagellin induce osteoclastogenesis and the production of cathelicidins, which can in turn inhibit osteoclastogenesis. Thus, cathelicidins contribute to maintaining microbiota-host homeostasis and promoting repair responses to inflammatory insults. In this review, we describe recent findings on the multiple roles of cathelicidins in host defense. We also discuss the significance of the human cathelicidin, LL-37, as a pharmaceutical target for the treatment of inflammation and bone loss in infectious diseases, such as periodontitis.

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References

  1. Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, Yu WH, Lakshmanan A, Wade WG. The human oral microbiome. J Bacteriol. 2010;192:5002–17.

    PubMed Central  PubMed  Google Scholar 

  2. Wade WG. The oral microbiome in health and disease. Pharmacol Res. 2013;69:137–43.

    PubMed  Google Scholar 

  3. Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol. 2011;11:505–18.

    PubMed  Google Scholar 

  4. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11:373–84.

    PubMed  Google Scholar 

  5. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–50.

    PubMed  Google Scholar 

  6. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415:389–95.

    PubMed  Google Scholar 

  7. Tomasinsig L, Zanetti M. The cathelicidins—structure, function and evolution. Curr Protein Pept Sci. 2005;6:23–34.

    PubMed  Google Scholar 

  8. Yount NY, Yeaman MR. Multidimensional signatures in antimicrobial peptides. Proc Natl Acad Sci USA. 2004;101:7363–8.

    PubMed Central  PubMed  Google Scholar 

  9. Peschel A, Sahl HG. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol. 2006;4:529–36.

    PubMed  Google Scholar 

  10. Zanetti M. The role of cathelicidins in the innate host defenses of mammals. Curr Issue Mol Biol. 2005;7:179–96.

    Google Scholar 

  11. Soehnlein O, Wantha S, Simsekyilmaz S, Doring Y, Megens RT, Mause SF, Drechsler M, Smeets R, Weinandy S, Schreiber F, Gries T, Jockenhoevel S, Moller M, Vijayan S, van Zandvoort MA, Agerberth B, Pham CT, Gallo RL, Hackeng TM, Liehn EA, Zernecke A, Klee D, Weber C. Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl Med. 2011;3:103ra98.

    PubMed Central  PubMed  Google Scholar 

  12. Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I, Hokfelt T, Gudmundsson GH, Gallo RL, Agerberth B, Brauner A. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006;12:636–41.

    PubMed  Google Scholar 

  13. Rosenberger CM, Gallo RL, Finlay BB. Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication. Proc Natl Acad Sci USA. 2004;101:2422–7.

    PubMed Central  PubMed  Google Scholar 

  14. Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L, Gennaro R. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem. 1997;272:13088–93.

    PubMed  Google Scholar 

  15. Horibe K, Nakamichi Y, Uehara S, Nakamura M, Koide M, Kobayashi Y, Takahashi N, Udagawa N. Roles of cathelicidin-related antimicrobial peptide in murine osteoclastogenesis. Immunology. 2013;140:344–51.

    PubMed  Google Scholar 

  16. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3:238–50.

    PubMed  Google Scholar 

  17. De Y, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, Oppenheim JJ, 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. 2000;192:1069–74.

    Google Scholar 

  18. Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D. 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. 2005;174:6257–65.

    PubMed  Google Scholar 

  19. Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe T, Issbrucker K, Unterberger P, Zaiou M, Lebherz C, Karl A, Raake P, Pfosser A, Boekstegers P, Welsch U, Hiemstra PS, Vogelmeier C, Gallo RL, Clauss M, Bals R. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111:1665–72.

    PubMed Central  PubMed  Google Scholar 

  20. Coffelt SB, Tomchuck SL, Zwezdaryk KJ, Danka ES, Scandurro AB. Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells. Mol Cancer Res. 2009;7:907–15.

    PubMed Central  PubMed  Google Scholar 

  21. Murakami M, Ohtake T, Dorschner RA, Gallo RL. Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J Dent Res. 2002;81:845–50.

    PubMed  Google Scholar 

  22. Puklo M, Guentsch A, Hiemstra PS, Eick S, Potempa J. Analysis of neutrophil-derived antimicrobial peptides in gingival crevicular fluid suggests importance of cathelicidin LL-37 in the innate immune response against periodontogenic bacteria. Oral Microbiol Immunol. 2008;23:328–35.

    PubMed Central  PubMed  Google Scholar 

  23. Nizet V, Gallo RL. Cathelicidins and innate defense against invasive bacterial infection. Scand J Infect Dis. 2003;35:670–6.

    PubMed  Google Scholar 

  24. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, Pestonjamasp V, Piraino J, Huttner K, Gallo RL. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;414:454–7.

    PubMed  Google Scholar 

  25. Kovach MA, Ballinger MN, Newstead MW, Zeng X, Bhan U, Yu FS, Moore BB, Gallo RL, Standiford TJ. Cathelicidin-related antimicrobial peptide is required for effective lung mucosal immunity in gram-negative bacterial pneumonia. J Immunol. 2012;189:304–11.

    PubMed Central  PubMed  Google Scholar 

  26. Yamasaki KDNA, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, Morhenn VB, Gallo RL. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975–80.

    PubMed  Google Scholar 

  27. Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol. 2012;12:503–16.

    PubMed Central  PubMed  Google Scholar 

  28. Hancock RE, Diamond G. The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol. 2000;8:402–10.

    PubMed  Google Scholar 

  29. Rosenfeld Y, Papo N, Shai Y. Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J Biol Chem. 2006;281:1636–43.

    PubMed  Google Scholar 

  30. Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, Roche FM, Mu R, Doho GH, Pistolic J, Powers JP, Bryan J, Brinkman FS, Hancock RE. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol. 2006;176:2455–64.

    PubMed  Google Scholar 

  31. Kandler K, Shaykhiev R, Kleemann P, Klescz F, Lohoff M, Vogelmeier C, Bals R. The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands. Int Immunol. 2006;18:1729–36.

    PubMed  Google Scholar 

  32. Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76:4176–82.

    PubMed Central  PubMed  Google Scholar 

  33. 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. 2008;283:30471–81.

    PubMed Central  PubMed  Google Scholar 

  34. Subramanian HGK, 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. 2011;286:44739–49.

    PubMed Central  PubMed  Google Scholar 

  35. Seil M, Kabre E, Nagant C, Vandenbranden M, Fontanils U, Marino A, Pochet S, Dehaye JP. Regulation by CRAMP of the responses of murine peritoneal macrophages to extracellular ATP. Biochim Biophys Acta. 2010;1798:569–78.

    PubMed  Google Scholar 

  36. North RA. Molecular physiology of P2X receptors. Physiol Rev. 2002;82:1013–67.

    PubMed  Google Scholar 

  37. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science. 1996;272:735–8.

    PubMed  Google Scholar 

  38. Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G. Tissue distribution of the P2X7 receptor. Neuropharmacology. 1997;36:1277–83.

    PubMed  Google Scholar 

  39. Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, Austin JS, Zaykin DV, Vander Meulen H, Costigan M, Herbert TA, Yarkoni-Abitbul M, Tichauer D, Livneh J, Gershon E, Zheng M, Tan K, John SL, Slade GD, Jordan J, Woolf CJ, Peltz G, Maixner W, Diatchenko L, Seltzer Z, Salter MW, Mogil JS. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med. 2012;18:595–9.

    PubMed Central  PubMed  Google Scholar 

  40. Elssner A, Duncan M, Gavrilin M, Wewers MD. A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J Immunol. 2004;172:4987–94.

    PubMed  Google Scholar 

  41. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013;190:1217–26.

    PubMed Central  PubMed  Google Scholar 

  42. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.

    PubMed Central  PubMed  Google Scholar 

  43. Lande RGJ, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schröder JM, Liu YJ, Gilliet M. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–9.

    PubMed  Google Scholar 

  44. Lande RGD, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, Bassett R, Amuro H, Fukuhara S, Ito T, Liu YJ, Gilliet M. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19.

    PubMed Central  PubMed  Google Scholar 

  45. Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D. Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. J Immunol. 2001;167:3329–38.

    PubMed  Google Scholar 

  46. Ciornei CD, Egesten A, Bodelsson M. Effects of human cathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro. Acta Anaesthesiol Scand. 2003;47:213–20.

    PubMed  Google Scholar 

  47. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60.

    PubMed  Google Scholar 

  48. de Jongh GJ, Zeeuwen PL, Kucharekova M, Pfundt R, van der Valk PG, Blokx W, Dogan A, Hiemstra PS, van de Kerkhof PC, Schalkwijk J. High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis. J Invest Dermatol. 2005;125:1163–73.

    PubMed  Google Scholar 

  49. Hata TR, Kotol P, Boguniewicz M, Taylor P, Paik A, Jackson M, Nguyen M, Kabigting F, Miller J, Gerber M, Zaccaro D, Armstrong B, Dorschner R, Leung DY, Gallo RL. History of eczema herpeticum is associated with the inability to induce human beta-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis. Br J Dermatol. 2010;163:659–61.

    PubMed Central  PubMed  Google Scholar 

  50. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB, Leung DY. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9.

    PubMed  Google Scholar 

  51. Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, Leung DY. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006;24:341–8.

    PubMed  Google Scholar 

  52. Carlsson G, Wahlin YB, Johansson A, Olsson A, Eriksson T, Claesson R, Hanstrom L, Henter JI. Periodontal disease in patients from the original Kostmann family with severe congenital neutropenia. J Periodontol. 2006;77:744–51.

    PubMed  Google Scholar 

  53. Putsep K, Carlsson G, Boman HG, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet. 2002;360:1144–9.

    PubMed  Google Scholar 

  54. Hosokawa I, Hosokawa Y, Komatsuzawa H, Goncalves RB, Karimbux N, Napimoga MH, Seki M, Ouhara K, Sugai M, Taubman MA, Kawai T. Innate immune peptide LL-37 displays distinct expression pattern from beta-defensins in inflamed gingival tissue. Clin Exp Immunol. 2006;146:218–25.

    PubMed Central  PubMed  Google Scholar 

  55. Turkoglu O, Emingil G, Kutukculer N, Atilla G. Gingival crevicular fluid levels of cathelicidin LL-37 and interleukin-18 in patients with chronic periodontitis. J Periodontol. 2009;80:969–76.

    PubMed  Google Scholar 

  56. Rosen G, Sela MN, Bachrach G. The antibacterial activity of LL-37 against Treponema denticola is dentilisin protease independent and facilitated by the major outer sheath protein virulence factor. Infect Immun. 2012;80:1107–14.

    PubMed Central  PubMed  Google Scholar 

  57. Dale BA, Fredericks LP. Antimicrobial peptides in the oral environment: expression and function in health and disease. Curr Issue Mol Biol. 2005;7:119–33.

    Google Scholar 

  58. Graves DT, Oates T, Garlet GP. Review of osteoimmunology and the host response in endodontic and periodontal lesions. J Oral Microbiol. 2011;3:5304.

    Google Scholar 

  59. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci USA. 1990;87:7260–4.

    PubMed Central  PubMed  Google Scholar 

  60. Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988;123:2600–2.

    PubMed  Google Scholar 

  61. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20:345–57.

    PubMed  Google Scholar 

  62. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–42.

    PubMed  Google Scholar 

  63. Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13:1015–24.

    PubMed Central  PubMed  Google Scholar 

  64. Sato N, Takahashi N, Suda K, Nakamura M, Yamaki M, Ninomiya T, Kobayashi Y, Takada H, Shibata K, Yamamoto M, Takeda K, Akira S, Noguchi T, Udagawa N. MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha. J Exp Med. 2004;200:601–11.

    PubMed Central  PubMed  Google Scholar 

  65. Uchiyama M, Nakamichi Y, Nakamura M, Kinugawa S, Yamada H, Udagawa N, Miyazawa H. Dental pulp and periodontal ligament cells support osteoclastic differentiation. J Dent Res. 2009;88:609–14.

    PubMed  Google Scholar 

  66. Supanchart C, Thawanaphong S, Makeudom A, Bolscher JG, Nazmi K, Kornak U, Krisanaprakornkit S. The antimicrobial peptide, LL-37, inhibits in vitro osteoclastogenesis. J Dent Res. 2012;91:1071–7.

    PubMed  Google Scholar 

  67. McCrudden MT, Orr DF, Yu Y, Coulter WA, Manning G, Irwin CR, Lundy FT. LL-37 in periodontal health and disease and its susceptibility to degradation by proteinases present in gingival crevicular fluid. J Clin Periodontol. 2013;40:933–41.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-oka Gobara, Shiojiri, Nagano, 399-0781, Japan

    Yuko Nakamichi & Naoyuki Takahashi

  2. Department of Oral Histology, Matsumoto Dental University, Nagano, Japan

    Kanji Horibe

  3. Department of Biochemistry, Matsumoto Dental University, Nagano, Japan

    Nobuyuki Udagawa

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  1. Yuko Nakamichi
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  2. Kanji Horibe
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  4. Nobuyuki Udagawa
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Nakamichi, Y., Horibe, K., Takahashi, N. et al. Roles of cathelicidins in inflammation and bone loss. Odontology 102, 137–146 (2014). https://doi.org/10.1007/s10266-014-0167-0

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