Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, China.
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital of Southeast University, Nanjing, China.
Front Immunol. 2021 Feb 25;12:634889. doi: 10.3389/fimmu.2021.634889. eCollection 2021.
The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. However, during IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown.
The study is designed to determine the effect of PPARγ on IgG-IC-triggered acute lung inflammation, and the underlying mechanisms, which might provide theoretical basis for therapy of acute lung inflammation.
Department of Pathogenic Biology and Immunology, Medical School of Southeast University.
Mice with down-regulated/up-regulated PPARγ activity or down-regulation of Early growth response protein 1 (Egr-1) expression, and the corresponding controls.
Acute lung inflammation is induced in the mice by airway deposition of IgG-IC. Activation of PPARγ is achieved by using its agonist Rosiglitazone or adenoviral vectors that could mediate overexpression of PPARγ. PPARγ activity is suppressed by application of its antagonist GW9662 or shRNA. Egr-1 expression is down-regulated by using the gene specific shRNA.
We find that during IgG-IC-induced acute lung inflammation, PPARγ expression at both RNA and protein levels is repressed, which is consistent with the results obtained from macrophages treated with IgG-IC. Furthermore, both and data show that PPARγ activation reduces IgG-IC-mediated pro-inflammatory mediators' production, thereby alleviating lung injury. In terms of mechanism, we observe that the generation of Egr-1 elicited by IgG-IC is inhibited by PPARγ. As an important transcription factor, Egr-1 transcription is substantially increased by IgG-IC in both and studies, leading to augmented protein expression, thus amplifying IgG-IC-triggered expressions of inflammatory factors association with their promoters.
During IgG-IC-stimulated acute lung inflammation, PPARγ activation can relieve the inflammatory response by suppressing the expression of its downstream target Egr-1 that directly binds to the promoter regions of several inflammation-associated genes. Therefore, regulation of PPARγ-Egr-1-pro-inflammatory mediators axis by PPARγ agonist Rosiglitazone may represent a novel strategy for blockade of acute lung injury.
配体激活转录因子过氧化物酶体增殖物激活受体（PPAR）γ在多种生物过程中发挥着关键作用，包括细胞代谢、分化、发育和免疫反应。然而，在免疫球蛋白 G 免疫复合物（IgG-IC）诱导的急性肺炎症中，其在肺组织中的表达和功能尚不清楚。
本研究旨在确定 PPARγ 对 IgG-IC 触发的急性肺炎症的影响及其潜在机制，为急性肺炎症的治疗提供理论依据。
东南大学医学院病原生物学与免疫学系。
PPARγ 活性下调/上调的小鼠及相应对照，早期生长反应蛋白 1（Egr-1）表达下调的小鼠及相应对照。
通过气道沉积 IgG-IC 诱导小鼠发生急性肺炎症。使用其激动剂罗格列酮或能够介导过表达 PPARγ 的腺病毒载体激活 PPARγ。应用其拮抗剂 GW9662 或 shRNA 抑制 PPARγ 活性。使用基因特异性 shRNA 下调 Egr-1 表达。
我们发现，在 IgG-IC 诱导的急性肺炎症中，PPARγ 的 RNA 和蛋白质水平表达均受到抑制，这与用 IgG-IC 处理的巨噬细胞的结果一致。此外， 和 数据均显示，PPARγ 激活可减少 IgG-IC 介导的促炎介质的产生，从而减轻肺损伤。就其机制而言，我们观察到 IgG-IC 诱导的 Egr-1 生成被 PPARγ 抑制。作为一种重要的转录因子，Egr-1 在 和 研究中均因 IgG-IC 而显著增加，导致蛋白表达增加，从而放大 IgG-IC 触发的炎症因子的表达与其启动子相关联。
在 IgG-IC 刺激的急性肺炎症中，PPARγ 激活可通过抑制其下游靶标 Egr-1 的表达来缓解炎症反应，Egr-1 可直接结合几个炎症相关基因的启动子区域。因此，PPARγ 激动剂罗格列酮通过调节 PPARγ-Egr-1-促炎介质轴可能代表一种阻断急性肺损伤的新策略。
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