tetano
Editor, Senior Moderator
PLoS Pathog. 2018 Apr 5;14(4):e1006955. doi: 10.1371/journal.ppat.1006955. eCollection 2018 Apr.
[h=1]Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.[/h] Namkoong H[SUP]1,[/SUP][SUP]2[/SUP], Ishii M[SUP]1[/SUP], Fujii H[SUP]3[/SUP], Yagi K[SUP]1[/SUP], Asami T[SUP]1[/SUP], Asakura T[SUP]1[/SUP], Suzuki S[SUP]1[/SUP], Hegab AE[SUP]1[/SUP], Kamata H[SUP]1[/SUP], Tasaka S[SUP]1[/SUP], Atarashi K[SUP]4[/SUP], Nakamoto N[SUP]5[/SUP], Iwata S[SUP]6,[/SUP][SUP]7[/SUP], Honda K[SUP]4[/SUP], Kanai T[SUP]5[/SUP], Hasegawa N[SUP]6[/SUP], Koyasu S[SUP]4,[/SUP][SUP]8[/SUP], Betsuyaku T[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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?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.
PMID: 29621339 DOI: 10.1371/journal.ppat.1006955
[h=1]Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.[/h] Namkoong H[SUP]1,[/SUP][SUP]2[/SUP], Ishii M[SUP]1[/SUP], Fujii H[SUP]3[/SUP], Yagi K[SUP]1[/SUP], Asami T[SUP]1[/SUP], Asakura T[SUP]1[/SUP], Suzuki S[SUP]1[/SUP], Hegab AE[SUP]1[/SUP], Kamata H[SUP]1[/SUP], Tasaka S[SUP]1[/SUP], Atarashi K[SUP]4[/SUP], Nakamoto N[SUP]5[/SUP], Iwata S[SUP]6,[/SUP][SUP]7[/SUP], Honda K[SUP]4[/SUP], Kanai T[SUP]5[/SUP], Hasegawa N[SUP]6[/SUP], Koyasu S[SUP]4,[/SUP][SUP]8[/SUP], Betsuyaku T[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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?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.
PMID: 29621339 DOI: 10.1371/journal.ppat.1006955