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Mannose-Binding Lectin Augments the Uptake of Lipid A, Staphylococcus aureus, and Escherichia coli by Kupffer Cells through Increased Cell Surface Expression of Scavenger Receptor A¹

Kei Ono^*,, Chiaki Nishitani^*,#, Hiroaki Mitsuzawa^*,#, Takeyuki Shimizu^*,#, Hitomi Sano^*,#, Hiroshi Suzuki, Tatsuhiko Kodama^¶, Nobuhiro Fujii, Koichi Fukase^||, Koichi Hirata and Yoshio Kuroki^2,*,#

^* Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan; First Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan; National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan; ^¶ Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan; ^|| Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan; and ^# Core Research for Engineering, Science, and Technology, Japan Science and Technology Agency, Kawaguchi, Japan

We investigated roles of scavenger receptor A (SR-A) and mannose-binding lectin (MBL) in the uptake of endotoxin and bacteria by Kupffer cells. When [³H]lipid A was injected into retro-orbital plexus of mice, significantly less accumulation of lipid A in the liver was observed in SR-A-deficient mice and wild-type mice coinjected with fucoidan or acetylated low-density lipoprotein, which are known ligands for SR-A. Isolated Kupffer cells were able to take up [³H]lipid A in a time-dependent manner. The amount of lipid A associated with nonadherent Kupffer cells derived from SR-A-deficient mice was reduced by 80% when compared with wild-type cells, indicating an important role of SR-A in endotoxin uptake by Kupffer cells. The lipid A uptake by Kupffer cells was significantly enhanced in the presence of rMBL. Coincubation of fucoidan with [³H]lipid A significantly inhibited the basal and the MBL-stimulated uptake of lipid A by Kupffer cells. Preincubation of MBL with Kupffer cells also increased the uptake of lipid A. These results indicate that MBL augments the SR-A-mediated uptake of lipid A by Kupffer cells. Consistently, the exposure of MBL to Kupffer cells increased cell surface SR-A expression. The phagocytosis of Staphylococcus aureus and Escherichia coli by Kupffer cells was also enhanced by preincubation of MBL with the cells. In addition, MBL bound to lipid A, LPS, and S. aureus, and precipitated S. aureus. This study demonstrates important roles of SR-A and MBL in the uptake of endotoxin and bacteria by Kupffer cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture.

² Address correspondence and reprint requests to Dr. Yoshio Kuroki, Department of Biochemistry, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku, Sapporo 060-8556, Japan. E-mail address: kurokiy{at}sapmed.ac.jp

³ Abbreviations used in this paper: SR-A, scavenger receptor A; AcLDL, acetylated low-density lipoprotein; MBL, mannose-binding lectin; wt, wild type.

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