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Tetraspanin CD9 Negatively Regulates Lipopolysaccharide-Induced Macrophage Activation and Lung Inflammation¹

Mayumi Suzuki^*, Isao Tachibana^2,*, Yoshito Takeda^*, Ping He^*,, Seigo Minami^*, Takeo Iwasaki^*, Hiroshi Kida^*, Sho Goya^*, Takashi Kijima^*, Mitsuhiro Yoshida^*, Toru Kumagai^*, Tadashi Osaki^* and Ichiro Kawase^*

^* Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan; and Department of Respiratory Medicine, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, People’s Republic of China

Tetraspanins facilitate the formation of multiple molecular complexes at specialized membrane microdomains and regulate cell activation and motility. In the present study, the role of tetraspanin CD9 in LPS-induced macrophage activation and lung inflammation was investigated in vitro and in vivo. When CD9 function was ablated with mAb treatment, small interfering RNA transfection, or gene knockout in RAW264.7 cells or bone marrow-derived macrophages, these macrophages produced larger amounts of TNF-, matrix metalloproteinase-2, and -9 upon stimulation with LPS in vitro, when compared with control cells. Sucrose gradient analysis revealed that CD9 partly colocalized with the LPS-induced signaling mediator, CD14, at low-density light membrane fractions. In CD9 knockout macrophages, CD14 expression, CD14 and TLR4 localization into the lipid raft, and their complex formation were increased whereas IB expression was decreased when compared with wild-type cells, suggesting that CD9 prevents the formation of LPS receptor complex. Finally, deletion of CD9 in mice enhanced macrophage infiltration and TNF- production in the lung after intranasal administration of LPS in vivo, when compared with wild-type mice. These results suggest that macrophage CD9 negatively regulates LPS response at lipid-enriched membrane microdomains.

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 by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a grant from Kansai Biomedical Cluster project in Saito, which is promoted by the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

² Address correspondence and reprint requests to Dr. Isao Tachibana, Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan. E-mail address: itachi02{at}imed3.med.osaka-u.ac.jp

³ Abbreviations used in this paper: TEM, tetraspanin-enriched microdomain; SIRP, signal regulatory protein ; 2OHpβCD, 2-hydroxypropyl-β-cyclodextrin; KO, knockout; BMDM, bone marrow-derived macrophage; WT, wild type; BALF, bronchoalveolar lavage fluid; siRNA, small interfering RNA; MMP, matrix metalloproteinase.