介导巨噬细胞坏死的 PTRF-IL33-ZBP1 信号促成了 HDM 诱导的气道炎症
2023/07/25
摘要
聚合酶 1 和转录物释放因子（PTRF，由 Cavin-1 编码）调节白细胞介素 33（IL-33）的释放，而 IL-33 与哮喘的发生有关。Z-DNA 结合蛋白 1（ZBP1）感应 Z-RNA 可诱导坏死，从而导致炎症性疾病。屋尘螨（HDM）是屋尘过敏原的主要来源，与哮喘的发生密切相关。PTRF是否通过IL-33和ZBP1介导HDM诱导的巨噬细胞坏死和气道炎症仍不清楚。在这里，我们发现在HDM诱导的哮喘小鼠模型中，缺乏PTRF可减少肺部IL-33、ZBP1、磷酸受体相互作用蛋白激酶3（p-RIPK3）和磷酸-混合系激酶结构域样（p-MLKL）（坏死执行者）以及气道炎症。在经 HDM 处理的巨噬细胞中，ZBP1、p-RIPK3 和 p-MLKL 的水平明显升高，而这些变化在缺失 Cavin-1 后被逆转。Il33的缺失也降低了HDM挑战肺中ZBP1、p-RIPK3和p-MLKL的表达。此外，IL-33与HDM协同作用可促进巨噬细胞中ZBP1、p-RIPK3和p-MLKL的表达。在支气管上皮细胞而非巨噬细胞和血管内皮细胞中，PTRF 能正向调节 IL-33 的表达。因此，我们得出结论，PTRF 介导了 HDM 诱导的巨噬细胞 ZBP1/ 坏死和气道炎症，支气管上皮细胞衍生的 IL-33 可增强这种效应。我们的研究结果表明，PTRF-IL33-ZBP1 信号通路可能是抑制气道炎症的一个有前景的靶点。
PTRF-IL33-ZBP1 signaling mediating macrophage necroptosis contributes to HDM-induced airway inflammation
Du, J., Liu, Y., Lan, G., Zhou, Y., Ni, Y., Liao, K., Zheng, F., Cheng, Q., Shi, G., & Su, X
Abstract
Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.
聚合酶 1 和转录物释放因子（PTRF，由 Cavin-1 编码）调节白细胞介素 33（IL-33）的释放，而 IL-33 与哮喘的发生有关。Z-DNA 结合蛋白 1（ZBP1）感应 Z-RNA 可诱导坏死，从而导致炎症性疾病。屋尘螨（HDM）是屋尘过敏原的主要来源，与哮喘的发生密切相关。PTRF是否通过IL-33和ZBP1介导HDM诱导的巨噬细胞坏死和气道炎症仍不清楚。在这里，我们发现在HDM诱导的哮喘小鼠模型中，缺乏PTRF可减少肺部IL-33、ZBP1、磷酸受体相互作用蛋白激酶3（p-RIPK3）和磷酸-混合系激酶结构域样（p-MLKL）（坏死执行者）以及气道炎症。在经 HDM 处理的巨噬细胞中，ZBP1、p-RIPK3 和 p-MLKL 的水平明显升高，而这些变化在缺失 Cavin-1 后被逆转。Il33的缺失也降低了HDM挑战肺中ZBP1、p-RIPK3和p-MLKL的表达。此外，IL-33与HDM协同作用可促进巨噬细胞中ZBP1、p-RIPK3和p-MLKL的表达。在支气管上皮细胞而非巨噬细胞和血管内皮细胞中，PTRF 能正向调节 IL-33 的表达。因此，我们得出结论，PTRF 介导了 HDM 诱导的巨噬细胞 ZBP1/ 坏死和气道炎症，支气管上皮细胞衍生的 IL-33 可增强这种效应。我们的研究结果表明，PTRF-IL33-ZBP1 信号通路可能是抑制气道炎症的一个有前景的靶点。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Cell Death Dis. 2023 Jul 15. DOI: 10.1038/s41419-023-05971-1)
(Cell Death Dis. 2023 Jul 15. DOI: 10.1038/s41419-023-05971-1)
PTRF-IL33-ZBP1 signaling mediating macrophage necroptosis contributes to HDM-induced airway inflammation
Du, J., Liu, Y., Lan, G., Zhou, Y., Ni, Y., Liao, K., Zheng, F., Cheng, Q., Shi, G., & Su, X
Abstract
Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.
