Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages

Yingji Jin, Isao Tachibana, Yoshito Takeda, Ping He, Sujin Kang, Mayumi Suzuki, Hanako Kuhara, Satoshi Tetsumoto, Kazuyuki Tsujino, Toshiyuki Minami, Takeo Iwasaki, Kaori Nakanishi, Satoshi Kohmo, Haruhiko Hirata, Ryo Takahashi, Koji Inoue, Izumi Nagatomo, Hiroshi Kida, Takashi Kijima, Mari ItoHideyuki Saya, Atsushi Kumanogoh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages.

Original languageEnglish
Article numbere73706
JournalPLoS One
Volume8
Issue number9
DOIs
Publication statusPublished - 2013 Sep 9

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Macrophages
Pneumonia
macrophages
Tetraspanins
inflammation
lungs
mice
anti-inflammatory activity
fluvastatin
gelatinase B
guanosinetriphosphatase
Anti-Inflammatory Agents
Up-Regulation
lipids
CD14 Antigens
respiratory tract diseases
Membrane Microdomains
Prenylation
Lipids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Jin, Y., Tachibana, I., Takeda, Y., He, P., Kang, S., Suzuki, M., ... Kumanogoh, A. (2013). Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages. PLoS One, 8(9), [e73706]. https://doi.org/10.1371/journal.pone.0073706

Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages. / Jin, Yingji; Tachibana, Isao; Takeda, Yoshito; He, Ping; Kang, Sujin; Suzuki, Mayumi; Kuhara, Hanako; Tetsumoto, Satoshi; Tsujino, Kazuyuki; Minami, Toshiyuki; Iwasaki, Takeo; Nakanishi, Kaori; Kohmo, Satoshi; Hirata, Haruhiko; Takahashi, Ryo; Inoue, Koji; Nagatomo, Izumi; Kida, Hiroshi; Kijima, Takashi; Ito, Mari; Saya, Hideyuki; Kumanogoh, Atsushi.

In: PLoS One, Vol. 8, No. 9, e73706, 09.09.2013.

Research output: Contribution to journalArticle

Jin, Y, Tachibana, I, Takeda, Y, He, P, Kang, S, Suzuki, M, Kuhara, H, Tetsumoto, S, Tsujino, K, Minami, T, Iwasaki, T, Nakanishi, K, Kohmo, S, Hirata, H, Takahashi, R, Inoue, K, Nagatomo, I, Kida, H, Kijima, T, Ito, M, Saya, H & Kumanogoh, A 2013, 'Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages', PLoS One, vol. 8, no. 9, e73706. https://doi.org/10.1371/journal.pone.0073706
Jin, Yingji ; Tachibana, Isao ; Takeda, Yoshito ; He, Ping ; Kang, Sujin ; Suzuki, Mayumi ; Kuhara, Hanako ; Tetsumoto, Satoshi ; Tsujino, Kazuyuki ; Minami, Toshiyuki ; Iwasaki, Takeo ; Nakanishi, Kaori ; Kohmo, Satoshi ; Hirata, Haruhiko ; Takahashi, Ryo ; Inoue, Koji ; Nagatomo, Izumi ; Kida, Hiroshi ; Kijima, Takashi ; Ito, Mari ; Saya, Hideyuki ; Kumanogoh, Atsushi. / Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages. In: PLoS One. 2013 ; Vol. 8, No. 9.
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AU - Minami, Toshiyuki

AU - Iwasaki, Takeo

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AU - Takahashi, Ryo

AU - Inoue, Koji

AU - Nagatomo, Izumi

AU - Kida, Hiroshi

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