Cathelicidin antimicrobial peptide explained

Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptideencoded in the human by the CAMP gene. The active form is LL-37. In humans, CAMP encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.[1] [2]

The cathelicidin family includes 30 types of which LL-37 is the only cathelicidin in the human.[3] Cathelicidins are stored in the secretory granules of neutrophils and macrophages and can be released following activation by leukocytes. Cathelicidin peptides are dual-natured molecules called amphiphiles: one end of the molecule is attracted to water and repelled by fats and proteins, and the other end is attracted to fat and proteins and repelled by water. Members of this family react to pathogens by disintegrating, damaging, or puncturing cell membranes.

Cathelicidins thus serve a critical role in mammalian innate immune defense against invasive bacterial infection. The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous. Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.[4]

Cathelicidin peptides have been isolated from many different species of mammals, including marsupials.[5] Cathelicidins are mostly found in neutrophils, monocytes, mast cells, dendritic cells and macrophages[6] after activation by bacteria, viruses, fungi, parasites or the hormone 1,25-D, which is the hormonally active form of vitamin D.[7] They have been found in some other cells, including epithelial cells and human keratinocytes.[8]

Etymology

The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins.[9] The name cathelin itself is coined from cathepsin L inhibitor in 1989.[10]

Mechanism of antimicrobial activity

The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.[11]

Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. Therefore, LL-37 can inhibit the formation of bacterial biofilms.[12]

Other activities

LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process.[13] All these mechanisms together play an essential role in tissue homeostasis and regenerative processes. Moreover, it has an agonistic effect on various pleiotropic receptors, for example, formyl peptide receptor like-1 (FPRL-1),[14] purinergic receptor P2X7, epidermal growth factor receptor (EGFR)[15] or insulin-like growth factor-1 receptor (IGF-1R).[16]

Furthermore, it induces angiogenesis[17] and regulates apoptosis.[18]

Characteristics

Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.[19] Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.[4]

In 1995, Gudmundsson et al. assumed that the active antimicrobial peptide is formed of a 39-residue C-terminal domain (termed FALL-39). However, only a year later stated that the matured AMP, now called LL-37, is in reality two amino acids shorter than FALL-39.[20] [21]

The cathelicidin family shares primary sequence homology with the cystatin[22] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.

Non-human orthologs

Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, horses and wallabies.[23] Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial.[24] About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans.[11] Currently identified cathelicidin peptides include the following:[4]

Clinical significance

Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea.[29] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.[30]

Lower plasma levels of human cathelicidin antimicrobial protein (hCAP18) appear to significantly increase the risk of death from infection in dialysis patients.[31] The production of cathelicidin is up-regulated by vitamin D.[32] [33]

SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.[34] In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms.[35]

LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate dendritic cells (a type of antigen presenting cell) which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation.[36] LL-37 has also been found to be a common auto-antigen in psoriasis; T-cells specific to LL-37 were found in the blood and skin in two thirds of patients with moderate to severe psoriasis.

LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. An imbalance between LL-37 and Ab may be a factor affecting AD-associated fibrils and plaques. Chronic, oral Porphyromonas gingivalis, and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia.[37] [38]

Applications

Research into the AMP family—particularly in regards to their mechanism of action—has been ongoing for nearly 20 years. Despite sustained interest, treatments derived or utilizing AMPs have not been widely adopted for clinical use for several reasons.[39] One, drug candidates from AMPs have a narrow window of bioavailability, because peptides are quickly broken down by proteases. Two, peptide drugs are more expensive than small molecule drugs to produce, which is problematic since peptide drugs must be given in large doses to counter rapid enzymatic breakdown. These qualities also limit routes of administration, typically to injection, infusion, or slow release therapy.[40]

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: CAMP cathelicidin antimicrobial peptide.
  2. Web site: UniProt . www.uniprot.org . 8 February 2024.
  3. Dürr U, Sudheendra U, Ramamoorthy, A . LL-37, the only human member of the cathelicidin family of antimicrobial peptides . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1758 . 9 . 1408–1425 . September 2006 . 10.1016/j.bbamem.2006.03.030 . 16716248 . free .
  4. Zanetti M . Cathelicidins, multifunctional peptides of the innate immunity . Journal of Leukocyte Biology . 75 . 1 . 39–48 . January 2004 . 12960280 . 10.1189/jlb.0403147 . 14902156 .
  5. Carman R, Simonian MR, Old JM, Jacques NA, Deane EM (2008). Immunohistochemistry using antibodies to the Cathelicidin LL37/hCAP18 in the tammar wallaby (Macropus eugenii). Tissue and Cell. 40(6), 459-466. DOI: 10.1016/j.tice.2008.05.002
  6. Vandamme D, Landuyt B, Luyten W, Schoofs L . A comprehensive summary of LL-37, the factotum human cathelicidin peptide . Cellular Immunology . 280 . 1 . 22–35 . November 2012 . 23246832 . 10.1016/j.cellimm.2012.11.009 .
  7. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL . 6 . Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response . Science . 311 . 5768 . 1770–3 . March 2006 . 16497887 . 10.1126/science.1123933 . 2006Sci...311.1770L . 52869005 .
  8. Bals R, Wang X, Zasloff M, Wilson JM . 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 . Proceedings of the National Academy of Sciences of the United States of America . 95 . 16 . 9541–6 . August 1998 . 9689116 . 10.1073/pnas.95.16.9541 . 21374 . 1998PNAS...95.9541B . free .
  9. Zanetti M, Gennaro R, Romeo D . Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain . FEBS Letters . 374 . 1 . 1–5 . October 1995 . 7589491 . 10.1016/0014-5793(95)01050-o . 34865828 .
  10. Ritonja A, Kopitar M, Jerala R, Turk V . Primary structure of a new cysteine proteinase inhibitor from pig leucocytes . FEBS Letters . 255 . 2 . 211–4 . September 1989 . 2792375 . 10.1016/0014-5793(89)81093-2 . free .
  11. Kościuczuk EM, Lisowski P, Jarczak J, Strzałkowska N, Jóźwik A, Horbańczuk J, Krzyżewski J, Zwierzchowski L, Bagnicka E . 6 . Cathelicidins: family of antimicrobial peptides. A review . Molecular Biology Reports . 39 . 12 . 10957–70 . December 2012 . 23065264 . 3487008 . 10.1007/s11033-012-1997-x .
  12. Dosler S, Karaaslan E . Inhibition and destruction of Pseudomonas aeruginosa biofilms by antibiotics and antimicrobial peptides . Peptides . 62 . 32–7 . December 2014 . 25285879 . 10.1016/j.peptides.2014.09.021 . 207359996 .
  13. Shaykhiev R, Beisswenger C, Kändler K, Senske J, Püchner A, Damm T, Behr J, Bals R . 6 . Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure . American Journal of Physiology. Lung Cellular and Molecular Physiology . 289 . 5 . L842-8 . November 2005 . 15964896 . 10.1152/ajplung.00286.2004 .
  14. 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 . The Journal of Experimental Medicine . 192 . 7 . 1069–74 . October 2000 . 11015447 . 10.1084/jem.192.7.1069 . 2193321 . free .
  15. von Haussen J, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, Reimer D, Wiewrodt R, Biesterfeld S, Aigner A, Czubayko F, Bals R . 6 . The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells . Lung Cancer . 59 . 1 . 12–23 . January 2008 . 17764778 . 10.1016/j.lungcan.2007.07.014 .
  16. 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 . 352–65 . January 2012 . 21685939 . 10.1038/onc.2011.239 . 3262900 . free .
  17. 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 PS, Vogelmeier C, Gallo RL, Clauss M, Bals R . 6 . An angiogenic role for the human peptide antibiotic LL-37/hCAP-18 . The Journal of Clinical Investigation . 111 . 11 . 1665–72 . June 2003 . 12782669 . 156109 . 10.1172/JCI17545 .
  18. Ren SX, Shen J, Cheng AS, Lu L, Chan RL, Li ZJ, Wang XJ, Wong CC, Zhang L, Ng SS, Chan FL, Chan FK, Yu J, Sung JJ, Wu WK, Cho CH . 6 . 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 . e63641 . 2013-05-20 . 23700428 . 3659029 . 10.1371/journal.pone.0063641 . 2013PLoSO...863641R . Nie D . free .
  19. Gennaro R, Zanetti M . Structural features and biological activities of the cathelicidin-derived antimicrobial peptides . Biopolymers . 55 . 1 . 31–49 . 2000 . 10931440 . 10.1002/1097-0282(2000)55:1<31::AID-BIP40>3.0.CO;2-9 .
  20. Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH . FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis . Proceedings of the National Academy of Sciences of the United States of America . 92 . 1 . 195–9 . January 1995 . 7529412 . 42844 . 10.1073/pnas.92.1.195 . 1995PNAS...92..195A . free .
  21. Gudmundsson GH, 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 . European Journal of Biochemistry . 238 . 2 . 325–32 . June 1996 . 8681941 . 10.1111/j.1432-1033.1996.0325z.x . free .
  22. Zaiou M, Nizet V, Gallo RL . Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence . The Journal of Investigative Dermatology . 120 . 5 . 810–6 . May 2003 . 12713586 . 10.1046/j.1523-1747.2003.12132.x . free .
  23. Carman RL, Old JM, Baker M, Jacques NA, Deane EM (2009). Identification and expression of a novel marsupial cathelicidin from the tammar wallaby (Macropus eugenii). Veterinary Immunology and Immunopathology. 127(3-4), 269-276. DOI: 10.1016/j.vetimm.2008.10.319
  24. Carman RL, Simonian MR, Old JM, Jacques NA, Deane EM . Immunohistochemistry using antibodies to the cathelicidin LL37/hCAP18 in the tammar wallaby, Macropus eugenii . Tissue & Cell . 40 . 6 . 459–466 . December 2008 . 18597803 . 10.1016/j.tice.2008.05.002 .
  25. 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 . The Journal of Biological Chemistry . 272 . 20 . 13088–93 . May 1997 . 9148921 . 10.1074/jbc.272.20.13088 . free .
  26. Hao X, Yang H, Wei L, Yang S, Zhu W, Ma D, Yu H, Lai R . Amphibian cathelicidin fills the evolutionary gap of cathelicidin in vertebrate . Amino Acids . 43 . 2 . 677–85 . August 2012 . 22009138 . 10.1007/s00726-011-1116-7 . 2794908 .
  27. Achanta M, Sunkara LT, Dai G, Bommineni YR, Jiang W, Zhang G . Tissue expression and developmental regulation of chicken cathelicidin antimicrobial peptides . Journal of Animal Science and Biotechnology . 3 . 1 . 15 . May 2012 . 22958518 . 3436658 . 10.1186/2049-1891-3-15 . free .
  28. Peel E, Cheng Y, Djordjevic JT, Fox S, Sorrell TC, Belov K . Cathelicidins in the Tasmanian devil (Sarcophilus harrisii) . Scientific Reports . 6 . 35019 . October 2016 . 27725697 . 10.1038/srep35019 . 5057115. 2016NatSR...635019P .
  29. Reinholz M, Ruzicka T, Schauber J . Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease . Annals of Dermatology . 24 . 2 . 126–35 . May 2012 . 22577261 . 3346901 . 10.5021/ad.2012.24.2.126 .
  30. Yamasaki K, Di Nardo A, 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 . Nature Medicine . 13 . 8 . 975–80 . August 2007 . 17676051 . 10.1038/nm1616 . 23470611 .
  31. Gombart AF, Bhan I, Borregaard N, Tamez H, Camargo CA, Koeffler HP, Thadhani R . Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis . Clinical Infectious Diseases . 48 . 4 . 418–24 . February 2009 . 19133797 . 6944311 . 10.1086/596314 . free .
  32. Zasloff M . Antimicrobial peptides of multicellular organisms . Nature . 415 . 6870 . 389–95 . January 2002 . 11807545 . 10.1038/415389a . 205028607 . 2002Natur.415..389Z .
  33. Kamen DL, Tangpricha V . Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity . Journal of Molecular Medicine . 88 . 5 . 441–50 . May 2010 . 20119827 . 2861286 . 10.1007/s00109-010-0590-9 .
  34. de Breij A, Riool M, Cordfunke RA, Malanovic N, de Boer L, Koning RI, Ravensbergen E, Franken M, van der Heijde T, Boekema BK, Kwakman PH, Kamp N, El Ghalbzouri A, Lohner K, Zaat SA, Drijfhout JW, Nibbering PH . 6 . The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms . Science Translational Medicine . 10 . 423 . eaan4044 . January 2018 . 29321257 . 10.1126/scitranslmed.aan4044 . free .
  35. van Gent ME, van der Reijden TJ, Lennard PR, de Visser AW, Schonkeren-Ravensbergen B, Dolezal N, Cordfunke RA, Drijfhout JW, Nibbering PH . 6 . Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin . Antibiotics . 11 . 5 . 673 . May 2022 . 10.3390/ANTIBIOTICS11050673 . 35625317 . 9137631 . free .
  36. Rendon A, Schäkel K . Psoriasis Pathogenesis and Treatment . International Journal of Molecular Sciences . 20 . 6 . 1475 . March 2019 . 30909615 . 6471628 . 10.3390/ijms20061475 . free .
  37. Kanagasingam S, Chukkapalli SS, Welbury R, Singhrao SK . Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer's Disease . Journal of Alzheimer's Disease Reports . 4 . 1 . 501–511 . December 2020 . 33532698 . 7835991 . 10.3233/ADR-200250 .
  38. Rizzo R . Controversial role of herpesviruses in Alzheimer's disease . PLOS Pathogens . 16 . 6 . e1008575 . June 2020 . 32555685 . 7302436 . 10.1371/journal.ppat.1008575 . Spindler KR . free .
  39. Web site: Biomimetics Research from the Barron Lab. 2021-10-22. web.stanford.edu.
  40. Web site: DePalma A . 2015-06-30. Peptides: New Processes, Lower Costs . 2021-11-30. GEN - Genetic Engineering and Biotechnology News. en-US.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Cathelicidin antimicrobial peptide".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.