title: Antimicrobial peptides inhibit polyinosinic-polycytidylic acid-induced immune responses.
abstract: Viral proteins and nucleic acids stimulate TLRs to elicit production of cytokines, chemokines, and IFNs. Because of their immunostimulatory activity, several TLR agonists are being developed as vaccine adjuvants and cancer immunotherapeutics. However, TLR signaling is modified by disease state, which could enhance or impair therapeutic efficacy. For example, in the skin of psoriasis patients, the human cationic antimicrobial peptide LL37 is highly expressed and binds to host DNA. Association with LL37 enhances DNA uptake into intracellular compartments, where it stimulates TLR9-dependent overproduction of IFNs. Polyinosinic-polycytidylic acid (poly(I:C)), an analog of viral dsRNA, is recognized by TLR3 and is currently in preclinical trials as an inducer of type I IFN. If LL37 similarly enhanced IFN production, use of poly(I:C) might be contraindicated in certain conditions where LL37 is elevated. In this study, we show that TLR3 signaling was not enhanced, but was dramatically inhibited, by LL37 or mouse cathelicidin-related antimicrobial peptide in macrophages, microglial cells, and dendritic cells. Inhibition correlated with formation of a strong complex between antimicrobial peptides and poly(I:C), which partially inhibited poly(I:C) binding to TLR3. Therefore, after injury or during existing acute or chronic inflammation, when LL37 levels are elevated, the therapeutic activity of poly(I:C) will be compromised. Our findings highlight the importance of using caution when therapeutically delivering nucleic acids as immunomodulators.
authors: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors: Maroof
authors: M
authors: Hasan
authors: Catarina
authors: C
authors: Ruksznis
authors: Yan
authors: Y
authors: Wang
authors: Cynthia Anne
authors: CA
authors: Leifer
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D054804:Cathelicidins / Q000276:immunology / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D056747:Immunomodulation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D007155:Immunologic Factors; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C