title: Bacterial sphingophospholipids containing non-hydroxy fatty acid activate murine macrophages via Toll-like receptor 4 and stimulate bacterial clearance.
abstract: Sphingobacterium spiritivorum has five unusual sphingophospholipids (SPLs). Our previous study determined the complete chemical structures of these SPLs. The compositions of the long-chain bases/fatty acids in the ceramide portion, isoheptadecasphingosine/isopentadecanoate or isoheptadecasphingosine/2-hydroxy isopentadecanoate, are characteristic. The immune response against bacterial lipid components is considered to play important roles in microbial infections. It is reported that several bacterial sphingolipids composed of ceramide are recognized by CD1-restricted T and NKT cells and that a non-peptide antigen is recognized by γδ T cells. In this study, we demonstrated that these bacterial SPLs activated murine bone marrow macrophages (BMMs) via Toll-like receptor (TLR) 4 but not TLR2, although they slightly activated CD1d-restricted NKT and γδT cells. Interestingly, this TLR 4-recognition pathway of bacterial SPLs involves the fatty acid composition of ceramide in addition to the sugar moiety. A non-hydroxy fatty acid composed of ceramide was necessary to activate murine BMMs. The bacterial survival was significantly higher in TLR4-KO mice than in TLR2-KO and wild-type mice. The results indicate that activation of the TLR4-dependent pathway of BMMs by SPLs induced an innate immune response and contributed to bacterial clearance.
authors.affiliation: Department of Bacteriology, Osaka City University Graduate School of Medicine, Osaka, Japan. fujiwara@med.osaka-cu.ac.jp
authors.forename: Nagatoshi
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Takashi
authors.initials: T
authors.lastname: Naka
authors.forename: Ikuya
authors.initials: I
authors.lastname: Yano
authors.forename: Shinji
authors.initials: S
authors.lastname: Maeda
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kuwata
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Takemasa
authors.initials: T
authors.lastname: Takii
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ogura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology; D015398:Signal Transduction; D045249:Sphingobacterium / Q000502:physiology*; D013107:Sphingolipids / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013107:Sphingolipids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha