title: Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway independent of CD14.
abstract: Lipopolysaccharide (LPS) is recognized by CD14 with Toll-like receptor 4 (TLR4), and initiates 2 major pathways of TLR4 signaling, the MyD88-dependent and TRIF-dependent signaling pathways. The MyD88-dependent pathway induces inflammatory responses such as the production of TNF-α, IL-6, and IL-12 via the activation of NFκB and MAPK. The TRIF-dependent pathway induces the production of type-I IFN, and RANTES via the activation of IRF-3 and NFκB, and is also important for the induction of adaptive immune responses. CD14 plays a critical role in initiating the TRIF-dependent signaling pathway response to LPS, to support the internalization of LPS via endocytosis. Here, we clearly demonstrate that intracellular delivery of LPS by LPS-formulated liposomes (LPS-liposomes) initiate only TRIF-dependent signaling via clathrin-mediated endocytosis, independent of CD14. In fact, LPS-liposomes do not induce the production of TNF-α and IL-6 but induce RANTES production in peritoneal macrophages. Additionally, LPS-liposomes could induce adaptive immune responses effectively in CD14-deficient mice. Collectively, our results strongly suggest that LPS-liposomes are useful as a TRIF-dependent signaling-based immune adjuvant without inducing unnecessary inflammation.
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Watanabe
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kumazawa
authors.forename: Joe
authors.initials: J
authors.lastname: Inoue
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes; D000939:Epitopes / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018946:Chemokine CCL5; D002966:Clathrin; D000939:Epitopes; D007074:Immunoglobulin G; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008081:Liposomes; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse
references.citation: J Biol Chem. 2005 Mar 25;280(12):11347-51
references.pmid: 15644310
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2380-4
references.pmid: 7681594
references.citation: J Control Release. 2009 Jan 5;133(1):18-23
references.pmid: 18930085
references.citation: J Immunol. 2005 Sep 15;175(6):3940-5
references.pmid: 16148141
references.citation: J Clin Invest. 1996 Oct 1;98(7):1533-8
references.pmid: 8833900
references.citation: Pharm Res. 2005 Oct;22(10):1627-33
references.pmid: 16180119
references.citation: J Biol Chem. 2001 Jun 15;276(24):21129-35
references.pmid: 11274165
references.citation: J Exp Med. 2003 Oct 6;198(7):1043-55
references.pmid: 14517278
references.citation: Nat Immunol. 2010 May;11(5):373-84
references.pmid: 20404851
references.citation: Trends Microbiol. 2004 Apr;12(4):186-92
references.pmid: 15051069
references.citation: J Immunol. 2007 Jan 1;178(1):584-91
references.pmid: 17182599
references.citation: Antimicrob Agents Chemother. 1980 Apr;17(4):544-8
references.pmid: 7396450
references.citation: Vaccine. 2007 Jan 22;25(6):1007-13
references.pmid: 17049678
references.citation: Pharm Res. 1992 Oct;9(10):1235-42
references.pmid: 1448419
references.citation: Adv Exp Med Biol. 2010;667:59-68
references.pmid: 20665200
references.citation: Immunity. 1996 Apr;4(4):407-14
references.pmid: 8612135
references.citation: Nat Immunol. 2011 Apr;12(4):344-51
references.pmid: 21358639
references.citation: Science. 2003 Aug 1;301(5633):640-3
references.pmid: 12855817
references.citation: Nat Immunol. 2005 Jun;6(6):565-70
references.pmid: 15895089
references.citation: J Cell Biol. 2005 Jan 31;168(3):465-76
references.pmid: 15668297
references.citation: J Invest Dermatol. 2007 Mar;127(3):614-21
references.pmid: 17159912
references.citation: Biol Pharm Bull. 2006 Feb;29(2):385-7
references.pmid: 16462052
references.citation: Science. 1990 Sep 21;249(4975):1431-3
references.pmid: 1698311
references.citation: Int Immunol. 2002 Jul;14(7):695-700
references.pmid: 12096028
references.citation: Curr Top Microbiol Immunol. 2002;270:109-20
references.pmid: 12467247
references.citation: Nature. 2005 Apr 21;434(7036):1035-40
references.pmid: 15815647
references.citation: J Immunol. 2001 May 1;166(9):5688-94
references.pmid: 11313410
references.citation: Nat Immunol. 2008 Apr;9(4):361-8
references.pmid: 18297073
references.citation: Methods Mol Biol. 1991;7:81-9
references.pmid: 21416349
references.citation: Immunity. 2011 May 27;34(5):637-50
references.pmid: 21616434
references.citation: Science. 2007 Jun 15;316(5831):1628-32
references.pmid: 17569868
references.citation: Nat Immunol. 2003 Nov;4(11):1144-50
references.pmid: 14556004
references.citation: J Control Release. 2005 Nov 28;108(2-3):294-305
references.pmid: 16209897
references.citation: J Biol Chem. 1998 Aug 7;273(32):20285-91
references.pmid: 9685378
references.citation: J Immunol. 2000 Oct 15;165(8):4272-80
references.pmid: 11035061
references.citation: Nat Rev Microbiol. 2005 Jan;3(1):36-46
references.pmid: 15608698
references.citation: Cell. 2011 Nov 11;147(4):868-80
references.pmid: 22078883
references.citation: J Immunol. 1998 Nov 15;161(10):5534-45
references.pmid: 9820530