PLoS Pathogens (Apr 2018)

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

DOI
https://doi.org/10.1371/journal.ppat.1006955
Journal volume & issue
Vol. 14, no. 4
p. e1006955

Abstract

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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 (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.