Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.
Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.
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DOI：
10.1371/journal.ppat.1006955
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发表时间：
2018-04
期刊：
影响因子：
6.7
通讯作者：
Betsuyaku T
中科院分区：
文献类型：
--
作者：
Namkoong H;Ishii M;Fujii H;Yagi K;Asami T;Asakura T;Suzuki S;Hegab AE;Kamata H;Tasaka S;Atarashi K;Nakamoto N;Iwata S;Honda K;Kanai T;Hasegawa N;Koyasu S;Betsuyaku T
大环内酯类由于其免疫调节特性而用于治疗各种炎症性疾病;然而，对其确切的作用机制知之甚少。在这项研究中，我们研究了骨髓源性抑制细胞（MDSC）样CD 11b +Gr-1+细胞在大环内酯类抗生素克拉霉素（CAM）在休克和流感后肺炎球菌肺炎小鼠模型以及人类中的功能意义。腹腔注射CAM可显著扩增未处理小鼠脾和肺CD 11b +Gr-1+细胞群。值得注意的是，CAM预处理提高了脂多糖（LPS）诱导的休克小鼠模型的存活率。此外，CAM处理的CD 11b +Gr-1+细胞的过继转移通过增加IL-10表达保护小鼠免受LPS诱导的致死性。CAM还改善了流感后CAM耐药肺炎球菌肺炎的存活率，改善了肺部病理学，降低了干扰素（IFN）-γ和增加了IL-10水平。CAM处理的CD 11b +Gr-1+细胞的连续转移保护小鼠免受流感后肺炎球菌肺炎。进一步的分析显示CAM诱导的CD 11b +Gr-1+细胞扩增依赖于STAT 3介导的Bv 8产生，并且可能通过肠道微生物群的存在而促进。最后，对口服CAM后从健康志愿者中获得的外周血进行的分析显示，人MDSC样细胞（谱系-HLA-DR-CD 11b + CD 33+）有扩增趋势，且端粒酶1 mRNA表达增加。因此，CAM促进了大环内酯类免疫调节特性所必需的免疫抑制性CD 11b +Gr-1+细胞的独特群体的扩增。髓源性抑制细胞（MDSC）是抗炎髓样祖细胞的异质群体，其响应于急性和慢性炎症以及各种疾病（如自身免疫性疾病和癌症）而扩增。大环内酯类抗生素克拉霉素在各种炎症性疾病中具有免疫调节作用，与其抗菌作用不同，但这些作用的机制尚不清楚。本研究表明，克拉霉素处理诱导脾和肺中CD 11b +Gr-1+ MDSC样细胞显著扩增，足以通过增加IL-10和降低IFN-γ水平保护小鼠免受LPS诱导的致死性和克拉霉素耐药细菌性肺炎。克拉霉素诱导的CD 11b +Gr-1+细胞扩增依赖于STAT 3介导的Bv 8产生。此外，克拉霉素治疗人体后，观察到免疫抑制性MDSC样细胞群扩增。总之，这些结果表明克拉霉素的免疫调节作用可归因于通过STAT 3/Bv 8轴诱导CD 11b +Gr-1+ MDSC样细胞。
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. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of anti-inflammatory myeloid progenitors that expand in response to acute and chronic inflammation as well as in various diseases, such as autoimmune diseases and cancer. The macrolide antibiotic clarithromycin has immunomodulatory effects in various inflammatory diseases, distinct from its antimicrobial effects, but the mechanism underlying these effects is unknown. 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. Clarithromycin-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production. Moreover, expansion of the immunosuppressive MDSC-like cell population was observed following clarithromycin treatment in humans. Collectively, these results suggest that the immunomodulatory effects of clarithromycin can be attributed to the induction of CD11b+Gr-1+ MDSC-like cells via the STAT3/Bv8 axis.
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影响因子：
6.4
作者：
Garg, Ankita;Spector, Stephen A.
通讯作者：
Spector, Stephen A.
CRTH2是中性粒细胞迁移和对多因素败血症的抗性的关键调节剂。
DOI：
10.4049/jimmunol.1102330
发表时间：
2012-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ishii M;Asano K;Namkoong H;Tasaka S;Mizoguchi K;Asami T;Kamata H;Kimizuka Y;Fujiwara H;Funatsu Y;Kagawa S;Miyata J;Ishii K;Nakamura M;Hirai H;Nagata K;Kunkel SL;Hasegawa N;Betsuyaku T
通讯作者：
Betsuyaku T
影响因子：
3.7
作者：
Curtis VF;Wang H;Yang P;McLendon RE;Li X;Zhou QY;Wang XF
通讯作者：
Wang XF
DOI：
10.1084/jem.177.2.547
发表时间：
1993-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gérard C;Bruyns C;Marchant A;Abramowicz D;Vandenabeele P;Delvaux A;Fiers W;Goldman M;Velu T
通讯作者：
Velu T
影响因子：
9.6
作者：
Friedlander, Adam L.;Albert, Richard K.
通讯作者：
Albert, Richard K.