Autophagy regulates accumulation and functional activity of granulocytic myeloid-derived suppressor cells via STAT3 signaling in endotoxin shock

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Dong, Guanjun¹  Si, Chuanping¹  Zhang, Qingqing¹  Yan, Fenglian¹  Li, Chunxia¹  Zhang, Hui^1,2  Ma, Qun¹  Dai, Jun¹  Li, Zhihua¹  Shi, Hui¹  Wang, Bo¹  Zhang, Junfeng¹  Ming, Jiankuo¹  Hu, Yuan²  Geng, Shuo³  Zhang, Yao³  Li, Liwu³  Xiong, Huabao^1,2 

[1] Jining Med Univ, Inst Immunol & Mol Med, Jining 272067, Shandong, Peoples R China

[2] Icahn Sch Med Mt Sinai, Dept Med, Immunol Inst, New York, NY 10029 USA

[3] Virginia Tech, Dept Biol Sci, Ctr Inflammat, Blacksburg, VA 24061 USA

关键词: Autophagy;    G-MDSCs;    Macrophage;    LPS;    ROS;    STAT3;   

DOI  :  10.1016/j.bbadis.2017.08.005

来源: Elsevier

【 摘 要 】

Autophagy extensively participates in immune responses and inflammatory diseases. Myeloid-derived suppressor cells (MDSCs) are derived from CD1113(+) Gri(+) cells under pathological conditions and play an immunosuppressive role in the pathogenesis of cancer and inflammatory diseases. However, the role of autophagy in regulating the accumulation and activity of MDSCs remains unknown. In the present study, we evaluated the effects and mechanisms of autophagy on regulating accumulation and activity of MDSCs. We first found that granulocytic MDSCs (G-MDSCs), but not monocytic MDSCs (M-MDSCs), were accumulated in mice challenged by lipopolysaccharide (LPS) and showed an elevated autophagy activity. Pharmacological inhibition of autophagy significantly enhanced accumulation of G-MDSCs in vivo and in vitro. Notably, inhibition of autophagy enhanced the immunosuppressive activity of G-MDSCs on M1 macrophage polarization by promoting reactive oxygen species (ROS) production. Inhibition of autophagy promotes the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in G-MDSCs, which is required for the accumulation and activity of MDSCs. In addition, in vivo pharmacological inhibition of autophagy significantly attenuated the condition of mice challenged by LPS. Thus, we conclude that inhibition of autophagy contributes to accumulation and immunosuppressive function of G-MDSCs by promoting the activation of STAT3 signaling, suggesting that autophagy may play a critical role in regulating accumulation and activity of MDSCs. Our study provides new insights into understanding the mechanisms of autophagy in regulating immune responses and pathogenesis of inflammatory diseases.

【 授权许可】

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