Identification of human cathelicidin peptide LL-37 as a ligand for macrophage integrin α_Mβ₂ (Mac-1, CD11b/CD18) that promotes phagocytosis by opsonizing bacteria

References

• Zanetti M.. The role of cathelicidins in the innate host defenses of mammals. In: Gallo RL, editor. Antimicrobial Peptides in Human Health and Disease. Norfolk, UK: Horizon Bioscience; 2005:15–50.
   Google Scholar
• Sørensen OE, Follin P, Johnsen AH, et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97:3951–3959.
   PubMed Web of Science ®Google Scholar
• Gundmundsson GH, Agerberth B.. Antimicrobial peptides in human blood. In: Gallo RL, editor. Antimicrobial Peptides in Human Health and Disease. Norfolk, UK: Horizon Bioscience; 2005:153–174.
   Google Scholar
• Bals R, Weiner DJ, Moscioni AD, Meegalla RL, Wilson JM. Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect Immun. 1999;67(11):6084–6089.
   PubMed Web of Science ®Google Scholar
• Cirioni O, Giacometti A, Ghiselli R, et al. LL-37 protects rats against lethal sepsis caused by gram-negative bacteria. Antimicrob Agents Chemother. 2006;50(5):1672–1679.
   PubMed Web of Science ®Google Scholar
• Bowdish DME, Davidson DJ, Lau YE, Lee K, Scott MG, Hancock REW. Impact of LL-37 on anti-infective immunity. J Leukoc Biol. 2005;77(4):451–459.
   PubMed Web of Science ®Google Scholar
• Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389–395.
   PubMed Web of Science ®Google Scholar
• McPhee JB, Hancock RE. Function and therapeutic potential of host defence peptides. J Pept Sci. 2005;11(11):677–687.
   Web of Science ®Google Scholar
• Bowdish DM, Davidson DJ, Hancock REW. A re-evaluation of the role of host defence peptides in mammalian immunity. Curr Protein Pept Sci. 2005;6(1):35–51.
   Web of Science ®Google Scholar
• Finlay BB, Hancock RE. Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol. 2004;2(6):497–504.
   PubMed Web of Science ®Google Scholar
• Mookherjee N, Hancock REW. Cationic host defense peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci. 2007;64(7–8):922–933.
   PubMed Web of Science ®Google Scholar
• Yang D, Chen Q, Schmidt AP, et al. 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, a T cells. J Exp Med. 2000;192(7):1069–1074.
   PubMed Web of Science ®Google Scholar
• Scott MG, Davidson DJ, Gold MR, Bowdish DM, Hancock REW. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune response. J Immunol. 2002;169(7):3883–3891.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Niyonsaba F, Ushio H, et al. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. Br J Dermatol. 2007;157(6):1124–1131.
   PubMed Web of Science ®Google Scholar
• 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. 2006;176(5):3044–3052.
   Web of Science ®Google Scholar
• Tjabringa GS, Aarbiou J, Ninaber DK, et al. The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. J Immunol. 2003;171(12):6690–6696.
   PubMed Web of Science ®Google Scholar
• 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(8):4987–4994.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Cherryholmes G, Chang F, Rose DM, Schraufstatter I, Shively JE. Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils. Eur J Immunol. 2009;39(11):3181–3194.
   Web of Science ®Google Scholar
• 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. 2011;286(52):44739–44749.
   Web of Science ®Google Scholar
• Podolnikova NP, Podolnikov AV, Haas TA, Lishko VK, Ugarova TP. Ligand recognition specificity of leukocyte integrin αMβ2 (Mac-1, CD11b/CD18) and its functional consequences. Biochemistry. 2015;54(6):1408–1420.
   PubMed Web of Science ®Google Scholar
• Moon JY, Henzler-Wildman KA, Ramamoorthy A. Expression and purification of a recombinant LL-37 from Escherichia coli. Biochim Biophys Acta. 2006;1758(9):1351–1358.
   Web of Science ®Google Scholar
• Yakubenko VP, Solovjov DA, Zhang L, Yee VC, Plow EF, Ugarova TP. Identification of the binding site for fibrinogen recognition peptide g383-395 within the αM I-domain of integrin αMβ2. J Biol Chem. 2001;276(17):13995–14003.
   Web of Science ®Google Scholar
• Lishko VK, Podolnikova NP, Yakubenko VP, et al. Multiple binding sites in fibrinogen for integrin αMβ2 (Mac-1). J Biol Chem. 2004;279(43):44897–44906.
   Web of Science ®Google Scholar
• Podolnikova NP, Gorkun OV, Loreth RM, Lord ST, Yee VC, Ugarova TP. A cluster of basic amino acid residues in the g370-381 sequence of fibrinogen comprises a binding site for platelet integrin αIIbβ3 (GPIIb/IIIa). Biochemistry. 2005;44(51):16920–16930.
   Web of Science ®Google Scholar
• Yakubenko VP, Lishko VK, Lam SCT, Ugarova TP. A molecular basis for integrin αMβ2 ligand binding promiscuity. J Biol Chem. 2002;277(50):48635–48642.
   Web of Science ®Google Scholar
• Lishko VK, Yakubenko VP, Ugarova TP. The interplay between integrins αMβ2 and α5β1 during cell migration to fibronectin. Exp Cell Res. 2003;283(1):116–126.
   Web of Science ®Google Scholar
• Wan M, van der Does AM, Tang X, Lindbom L, Agerberth B, Haeggström JZ. Antimicrobial peptide LL-37 promotes bacterial phagocytosis by human macrophages. J Leukoc Biol. 2014;95(6):971–981.
   PubMed Web of Science ®Google Scholar
• 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. Eur J Biochem. 1996;238(2):325–332.
   Google Scholar
• Moyle M, Foster DL, McGrath DE, et al. A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18. J Biol Chem. 1994;269(13):10008–10015.
   Web of Science ®Google Scholar
• Chen N, Chen CC, Lau LF. Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface sulfate proteoglycans. J Biol Chem. 2000;275(32):24953–24961.
   Web of Science ®Google Scholar
• Schober JM, Chen N, Grzeszkiewicz T, et al. Identification of integrin aMb2 as an adhesion receptor on peripheral blood monocytes for Cyr61 and connective tissue growth factor, immediate-early gene products expressed in atherosclerotic lesions. Blood. 2002;99(12):4457–4465.
   Web of Science ®Google Scholar
• Wang G. Structure of human host defense cathelicidin LL-37 and its smallest antimicrobial peptide KR-12 in lipid micelles. J Biol Chem. 2008;283(47):32637–32643.
   Web of Science ®Google Scholar
• Ugarova TP, Solovjov DA, Zhang L, et al. Identification of a novel recognition sequence for integrin αMβ2 within the gamma-chain of fibrinogen. J Biol Chem. 1998;273(35):22519–22527.
   Web of Science ®Google Scholar
• Flick MJ, Du X, Witte DP, et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest. 2004;113(11):1596–1606.
   PubMed Web of Science ®Google Scholar
• Johansson J, Gudmundsson GH, Rottenberg ME, Berndt KD, Agerberth B. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J Biol Chem. 1998;273(6):3718–3724.
   PubMed Web of Science ®Google Scholar
• Zelezetsky I, Pontillo A, Puzzi L, et al. Evolution of the primate cathelicidin. Correlation between structural variations and antimicrobial activity. J Biol Chem. 2006;281(29):19861–19871.
   Web of Science ®Google Scholar
• Niyonsaba F, Iwabuchi K, Someya A, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology. 2002;106(1):20–26.
   PubMed Web of Science ®Google Scholar
• Koczulla R, von Degemfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111(11):1665–1672.
   PubMed Web of Science ®Google Scholar
• Matsuzaki K. Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochim Biophys Acta. 1999;1462(1–2):1–10.
   Web of Science ®Google Scholar
• Coxon A, Rieu P, Barkalow FJ, et al. A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity. 1996;5(6):653–666.
   PubMed Web of Science ®Google Scholar
• Lu H, Smith CW, Perrard J, et al. LFA-1 is sufficient in mediating neutrophil emigration in Mac-1 deficient mice. J Clin Invest. 1997;99(6):1340–1350.
   Web of Science ®Google Scholar
• Kuroda K, Okumura K, Isogai H, Isogai E. The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. Front Oncol. 2015;5:144.
   PubMed Web of Science ®Google Scholar
• Ding ZM, Babensee JE, Simon SI, et al. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol. 1999;163(9):5029–5038.
   PubMed Web of Science ®Google Scholar
• Henderson RB, Lim LHK, Tessier PA, et al. The use of lymphocyte function-associated antigen (LFA)-1-deficient mice to determine the role of LFA-1, Mac-1, and α4 integrin in the inflammatory response of neutrophils. J Exp Med. 2001;194(2):219–226.
   PubMed Web of Science ®Google Scholar
• Zhang X, Bajic G, Andersen GR, Christiansen SH, Vorup-Jensen T. The cationic peptide LL-37 binds Mac-1 (CD11b/CD18) with a low dissociation rate and promotes phagocytosis. Biochim Biophys Acta. 2016;1864(5):471–478.
   PubMed Web of Science ®Google Scholar
• Schaller-Bals S, Schulze A, Bals R. Increased levels of antimicrobial peptides in tracheal aspirates of newborn infants during infection. Am J Respir Crit Care Med. 2002;165(7):992–995.
   Web of Science ®Google Scholar
• Chromek M, Slamová Z, Bergman P, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006;12(6):636–641.
   PubMed Web of Science ®Google Scholar
• 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(9):4176–4182.
   PubMed Web of Science ®Google Scholar
• Ross GD, Lambris JD. Identification of a C3bi-specific membrane complement receptor that is expressed on lymphocytes, monocytes, neutrophils, and erythrocytes. J Exp Med. 1982;155(1):96–110.
   Web of Science ®Google Scholar
• Ross GD, Cain JA, Lachmann PJ. Membrane complement receptor type three (CR3) has lectin-like properties analogous to bovine conglutinin as functions as a receptor for zymosan and rabbit erythrocytes as well as a receptor for iC3b. J Immunol. 1985;134(5):3307–3315.
   Web of Science ®Google Scholar
• Heinzelmann M, Platz A, Flodgaard H, Miller FN. Heparin binding protein (CAP37) is an opsonin for Staphylococcus aureus and increases phagocytosis in monocytes. Inflammation. 1998;22(5):493–507.
   Web of Science ®Google Scholar
• Fleischmann J, Selsted ME, Lehrer RI. Opsonic activity of MCP-1 and MCP-2, cationic peptides from rabbit alveolar macrophages. Diagn Microbiol Infect Dis. 1985;3(3):233–242.
   Web of Science ®Google Scholar
• Sol A, Ginesin O, Chaushu S, et al. LL-37 opsonizes and inhibits biofilm formation of Aggregatibacter actinomycetemcomitans at subbactericidal concentrations. Infect Immun. 2013;81(10):3577–3585.
   Web of Science ®Google Scholar
• Soehnlein O, Kenne E, Rotzius P, Eriksson EE, Lindbom L. Neutrophil secretion products regulate anti-bacterial activity in monocytes and macrophages. Clin Exp Immunol. 2008;151(1):139–145.
   Web of Science ®Google Scholar
• Ross GD, Vetvicka V. CR3(CD11b,CD18): a phagocyte and NK cell membrane receptor with miltiple ligand specificities and functions. Clin Exp Immunol. 1993;92(2):181–184.
   PubMed Web of Science ®Google Scholar
• Ichinose M, Asai M, Sawada M. Enhancement of phagocytosis by dynorphin A in mouse peritoneal macrophages. J Neuroimmunol. 1995;60(1–2):37–43.
   PubMed Web of Science ®Google Scholar
• Podolnikova NP, Brothwell JA, Ugarova TP. The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (αMβ2, CD11b/CD18). Mol Pain. 2015;11:33.
   Web of Science ®Google Scholar
• Zhang L, Harris SM, Falla TJ.. Therapeutic applications of innate immunity peptides. In: Gallo RL, editor. Antimicrobial Peptides in Human Health and Disease. Norfolk: Horizon Bioscience; 2005:331–360.
   Google Scholar
• Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24(12):1551–1557.
   PubMed Web of Science ®Google Scholar
• Duplantier AJ, van Hoek ML. The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicrobial infected wounds. Front Immunol. 2013;4:143.
   PubMed Web of Science ®Google Scholar