title: Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.
abstract: Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico ; Cell Biology Department, Center for Research and Advanced Studies of the National Polytechnic Institute (IPN), 07360 Mexico City, DF, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Wong-Baeza
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Alonso
authors.initials: A
authors.lastname: Tescucano
authors.affiliation: Oncology Department, Mexican Institute of Social Security, XXI Century National Medical Center, 06720 Mexico City, DF, Mexico.
authors.forename: Horacio
authors.initials: H
authors.lastname: Astudillo
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Albany
authors.initials: A
authors.lastname: Reséndiz
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Carla
authors.initials: C
authors.lastname: Landa
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Luis
authors.initials: L
authors.lastname: España
authors.affiliation: Immunology Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Jeanet
authors.initials: J
authors.lastname: Serafín-López
authors.affiliation: Immunology Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Iris
authors.initials: I
authors.lastname: Estrada-García
authors.affiliation: Immunology Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Estrada-Parra
authors.affiliation: Cell Biology Department, Center for Research and Advanced Studies of the National Polytechnic Institute (IPN), 07360 Mexico City, DF, Mexico.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Flores-Romo
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Wong
authors.affiliation: Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.
authors.forename: Isabel
authors.initials: I
authors.lastname: Baeza
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D002746:Chlorpromazine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004075:Diglycerides / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005408:Flagellin / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000737:chemistry / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry / Q000494:pharmacology; D010718:Phosphatidylserines / Q000737:chemistry / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D008081:Liposomes; D009842:Oligopeptides; D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D005408:Flagellin; D002746:Chlorpromazine