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

被引：41

作者：

Namkoong, Ho ^{[1
,2
]}

Ishii, Makoto ^{[1
]}

Fujii, Hideki ^{[3
,9
]}

Yagi, Kazuma ^{[1
]}

Asami, Takahiro ^{[1
]}

Asakura, Takanori ^{[1
]}

Suzuki, Shoji ^{[1
]}

Hegab, Ahmed E. ^{[1
]}

Kamata, Hirofumi ^{[1
]}

Tasaka, Sadatomo ^{[1
]}

Atarashi, Koji ^{[4
]}

Nakamoto, Nobuhiro ^{[5
]}

Iwata, Satoshi ^{[6
,7
]}

Honda, Kenya ^{[4
]}

Kanai, Takanori ^{[5
]}

Hasegawa, Naoki ^{[6
]}

Koyasu, Shigeo ^{[4
,8
]}

Betsuyaku, Tomoko ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Med, Div Pulm Med, Tokyo, Japan

[2] Japan Soc Promot Sci, Tokyo, Japan

[3] Univ Ryukyus, Grad Sch Med, Dept Immunol, Okinawa, Japan

[4] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo, Japan

[5] Keio Univ, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Tokyo, Japan

[6] Keio Univ, Sch Med, Ctr Infect Dis & Infect Control, Tokyo, Japan

[7] Keio Univ, Sch Med, Dept Infect Dis, Tokyo, Japan

[8] RIKEN, Ctr Integrat Med Sci, Lab Immune Cell Syst, Yokohama, Kanagawa, Japan

[9] Tokushima Univ, Grad Sch Biomed Sci, Dept Oral Microbiol, Tokushima, Japan

来源：

PLOS PATHOGENS | 2018年 / 14卷 / 04期

基金：

日本学术振兴会;

关键词：

TUMOR-NECROSIS-FACTOR; SUPPRESSOR-CELLS; IFN-GAMMA; INTERLEUKIN-10; PRODUCTION; PNEUMOCOCCAL PNEUMONIA; INTERFERON-GAMMA; LONG-TERM; MACROLIDE; VIRUS; ACTIVATION;

D O I：

10.1371/journal.ppat.1006955

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 naive 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)-gamma 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.

引用

页数：30

共 59 条

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