Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS.
Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS.
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Beta-防御素 2 和 3 通过下调早期生长反应基因 1 和 c-FOS 抑制巨噬细胞自噬，促进铜绿假单胞菌的细菌清除
DOI：
10.3389/fimmu.2018.00211
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Wu Y;Li D;Wang Y;Liu X;Zhang Y;Qu W;Chen K;Francisco NM;Feng L;Huang X;Wu M
β-防御素2和3（BD 2和BD 3）是存在于感染部位的诱导肽，并且它们的抗微生物活性和免疫调节功能被充分表征。然而，没有研究彻底调查他们的免疫调节作用对巨噬细胞介导的免疫反应，对铜绿假单胞菌（PA）。在这里，我们使用THP-1和RAW264.7细胞系，并证明BD 2和BD 3抑制巨噬细胞自噬，但增强吞噬PA和酵母多糖生物颗粒以及吞噬溶酶体的形成，使用免疫荧光染色和共聚焦显微镜。平板计数法显示，BD 2和BD 3促进巨噬细胞介导的吞噬和对PA的胞内杀伤。此外，芯片和实时荧光PCR显示，两个基因，早期生长反应基因1（EGR 1）和c-FOS的表达，被BD 2和BD 3减弱。Western blot结果显示，BD 2和BD 3可抑制EGFR 1和c-FOS的表达和核转位。通过siRNA转染敲低EGR 1和c-FOS抑制PA感染前后的巨噬细胞自噬;而这两种转录因子的过表达增强自噬，但逆转BD 2和BD 3对巨噬细胞介导的PA根除的作用。总之，这些结果证明了BD 2和BD 3的新型免疫防御活性，其通过下调EGFR 1和c-FOS抑制巨噬细胞自噬来促进PA的清除。
Beta-defensins 2 and 3 (BD2 and BD3) are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA). Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1) and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS.
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发表时间：
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期刊：
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