title: Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells.
abstract: In this report we show that carrier-mediated delivery of mRNA may activate TLR3 signaling in respiratory cells. This activation of the innate immune system was accompanied with a massive production of type 1 interferons and other immunostimulating cytokines. The recognition of mRNA by the innate immune system was also associated with cell death, which proceeded in human respiratory cells via pyroptosis, a form of programmed cell death mediated by substantial overexpression of caspase-1. This indicated that the delivered mRNA is most likely also recognized by NOD-like receptors which regulate caspase-1 production. The viability of murine respiratory cells was less affected by mRNA transfection, which is in line with the lower transfection efficiency, lower innate immune response and the absence of a massive caspase-1 upregulation in these cells. Finally, we also demonstrated that the recognition of the delivered mRNA by the innate immune system had a negative effect on mRNA translation.
authors: Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, B-9820 Merelbeke, Belgium.
authors: Oliwia
authors: O
authors: Andries
authors: Marina
authors: M
authors: De Filette
authors: Stefaan C
authors: SC
authors: De Smedt
authors: Jo
authors: J
authors: Demeester
authors: Mario
authors: M
authors: Van Poucke
authors: Luc
authors: L
authors: Peelman
authors: Niek N
authors: NN
authors: Sanders
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008081:Liposomes; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000008:administration & dosage*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014162:Transfection
chemical_list: D016207:Cytokines; D008081:Liposomes; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D004247:DNA; D008156:Luciferases