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

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

doi:10.1371/journal.ppat.1006955

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 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.

Highlights

Macrolides have immunomodulatory properties in addition to their antibacterial effects [1, 2]
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of antiinflammatory myeloid progenitors that expand in response to acute and chronic inflammation as well as in various diseases, such as autoimmune diseases and cancer
The present study demonstrates that clarithromycin treatment induces a marked expansion of CD11b+Gr-1+ MDSC-like cells in the spleen and lungs, sufficient to protect mice from LPS-induced lethality and clarithromycin-resistant bacterial pneumonia via increased IL-10 and decreased IFN-γ levels

Summary

Introduction

Macrolides have immunomodulatory properties in addition to their antibacterial effects [1, 2]. Previous clinical trials have shown that macrolides exhibit clinical benefits for various pulmonary diseases, including diffuse panbronchiolitis [3], chronic obstructive pulmonary disease [4], acute respiratory distress syndrome [5], cystic fibrosis [6], and non-cystic fibrosis bronchiectasis [7]. Previous studies of macrolides have focused on their in vitro effects on isolated cells, such as immune cells, epithelial cells, endothelial cells, and fibroblasts [8]. Macrolides inhibit the production of pro-inflammatory cytokines [9]; the effects of macrolides on specific immune cell populations have not been examined. We hypothesized that the immunomodulatory properties of macrolides are physiological in origin, as they exhibit globally beneficial effects for various inflammatory diseases with different pathogenesis

Results

Discussion

Conclusion