Bacterial sphingophospholipids containing non-hydroxy fatty acid activate murine macrophages via Toll-like receptor 4 and stimulate bacterial clearance |
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| Authors: | Nagatoshi Fujiwara Steven A Porcelli Takashi Naka Ikuya Yano Shinji Maeda Hirotaka Kuwata Shizuo Akira Satoshi Uematsu Takemasa Takii Hisashi Ogura Kazuo Kobayashi |
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| Institution: | 1. Department of Bacteriology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA;3. MBR Co., Ltd., Osaka 567-0085, Japan;4. Japan BCG Laboratory, Tokyo 204-0022, Japan;5. Molecular Epidemiology Division, Mycobacterium Reference Center, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo 204-8533, Japan;6. Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;g Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;h Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;i Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan;j Department of Virology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;k Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan |
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| 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. |
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| Keywords: | SPL sphingophospholipid GSL glycosphingolipid BMM bone marrow macrophage |
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