Clarithromycin expands CD11b+Gr-1+cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia

Ho Namkoong, Makoto Ishii, Hideki Fujii, Kazuma Yagi, Takahiro Asami, Takanori Asakura, Shoji Suzuki, Ahmed E. Hegab, Hirofumi Kamata, Sadatomo Tasaka, Koji Atarashi, Nobuhiro Nakamoto, Satoshi Iwata, Kenya Honda, Takanori Kanai, Naoki Hasegawa, Shigeo Koyasu, Tomoko Betsuyaku

研究成果: Article

10 引用 (Scopus)

抄録

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (LineageHLA-DRCD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+cells essential for the immunomodulatory properties of macrolides.

元の言語English
記事番号e1006955
ジャーナルPLoS Pathogens
14
発行部数4
DOI
出版物ステータスPublished - 2018 4 1

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Bacterial Pneumonia
Clarithromycin
Septic Shock
Human Influenza
Pneumococcal Pneumonia
Macrolides
Adoptive Transfer
Interleukin-10
Lipopolysaccharides
Shock
Arginase
Lung
Survival
Immunosuppressive Agents
Interferons
Population
Oral Administration
Healthy Volunteers
Pathology
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

これを引用

Clarithromycin expands CD11b+Gr-1+cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. / Namkoong, Ho; Ishii, Makoto; Fujii, Hideki; Yagi, Kazuma; Asami, Takahiro; Asakura, Takanori; Suzuki, Shoji; Hegab, Ahmed E.; Kamata, Hirofumi; Tasaka, Sadatomo; Atarashi, Koji; Nakamoto, Nobuhiro; Iwata, Satoshi; Honda, Kenya; Kanai, Takanori; Hasegawa, Naoki; Koyasu, Shigeo; Betsuyaku, Tomoko.

:: PLoS Pathogens, 巻 14, 番号 4, e1006955, 01.04.2018.

研究成果: Article

Namkoong, Ho ; Ishii, Makoto ; Fujii, Hideki ; Yagi, Kazuma ; Asami, Takahiro ; Asakura, Takanori ; Suzuki, Shoji ; Hegab, Ahmed E. ; Kamata, Hirofumi ; Tasaka, Sadatomo ; Atarashi, Koji ; Nakamoto, Nobuhiro ; Iwata, Satoshi ; Honda, Kenya ; Kanai, Takanori ; Hasegawa, Naoki ; Koyasu, Shigeo ; Betsuyaku, Tomoko. / Clarithromycin expands CD11b+Gr-1+cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. :: PLoS Pathogens. 2018 ; 巻 14, 番号 4.
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abstract = "Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+cell populations in na{\"i}ve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+cells essential for the immunomodulatory properties of macrolides.",
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AU - Fujii, Hideki

AU - Yagi, Kazuma

AU - Asami, Takahiro

AU - Asakura, Takanori

AU - Suzuki, Shoji

AU - Hegab, Ahmed E.

AU - Kamata, Hirofumi

AU - Tasaka, Sadatomo

AU - Atarashi, Koji

AU - Nakamoto, Nobuhiro

AU - Iwata, Satoshi

AU - Honda, Kenya

AU - Kanai, Takanori

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