title: B cell-intrinsic toll-like receptor 7 is responsible for the enhanced anti-PEG IgM production following injection of siRNA-containing PEGylated lipoplex in mice.
abstract: Recently, we reported that immunostimulatory siRNA-containing PEGylated lipoplex (PEGylated siRNA-lipoplex) activates the immune system, resulting in the enhanced production of anti-PEG IgM. However, the enhancing mechanism upon anti-PEG IgM production has not been fully elucidated. In this study, we employed toll-like receptor 7 knock out (TLR7 KO) mice, and showed how PEGylated siRNA-lipoplex activates the innate immune system through TLR7 and consequently enhances anti-PEG IgM production. In addition, we showed that SCID mice reconstituted with TLR7-deficient B cells failed to enhance anti-PEG IgM production following the injection of PEGylated siRNA-lipoplex, but that SCID mice reconstituted with wild type B cells did enhance anti-PEG IgM production. These results suggest that immune activation via B cell-intrinsic TLR7, but not other TLR7-expressing cells, contributes predominantly to an enhanced anti-PEG IgM production in response to the intravenous injection of PEGylated siRNA-lipoplexes. A strategy to evade B cell-intrinsic TLR7 activation by siRNA, such as chemical modification, may overcome immunological barriers to PEGylated liposome-based siRNA therapeutics.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address: ishida@tokushima-u.ac.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D007075:Immunoglobulin M / Q000276:immunology*; D008081:Liposomes; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013154:Spleen / Q000166:cytology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D007075:Immunoglobulin M; D008081:Liposomes; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D011092:Polyethylene Glycols
keywords: Anti-PEG IgM; Innate immunity; PEGylated liposome; Small interfering RNA (siRNA); Toll-like receptor 7 (TLR7)