title: Endogenous intracellular cathelicidin enhances TLR9 activation in dendritic cells and macrophages.
abstract: Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type 1 IFN production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. In this study, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow-derived dendritic cells from Camp(-/-) mice have impaired CpG responses and Camp(-/-) mice had impaired response to CpG given i.v. or s.c. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects.
authors.affiliation: Division of Dermatology, University of California, San Diego, San Diego, CA 92161.
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Division of Dermatology, University of California, San Diego, San Diego, CA 92161 rgallo@ucsd.edu.
authors.forename: Richard L
authors.identifier: http://orcid.org/0000-0002-1401-7861
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C527702:CpG ODN 2395; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D016178:Granulocyte-Macrophage Colony-Stimulating Factor