GBP5通过NLRP3炎症小体激活加重急性肺损伤，同时诱导HIF-1α-CD73腺苷反馈环
GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α-CD73-adenosine Feedback Loop.
摘要(中文译文)
鸟苷酸结合蛋白5（GBP5）是一种干扰素诱导的GTP酶，可促进NLRP3炎症小体活化。然而，其在急性肺损伤（ALI）中的作用及其与代偿性抗炎通路的关系仍不明确。方法：我们采用LPS诱导的ALI小鼠模型，通过AAV介导的气管内GBP5敲低、转录组分析（RNA-seq）以及THP-1巨噬细胞的体外研究。利用GBP5过表达和CD73过表达来解析GBP5-HIF-1α-CD73-腺苷轴。对LPS诱导肺损伤的RNA-seq分析显示，GBP家族成员（尤其是GBP5）及多个腺苷代谢基因上调。在雄性C57BL/6小鼠（6-8周，每组n=10）中，AAV介导的GBP5敲低减轻了LPS诱导的肺损伤，减少了NLRP3炎症小体活化（NLRP3、ASC、cleaved caspase-1），并降低了炎性细胞因子水平（IL-1β、IL-6、TNF-α）。同时，GBP5敲低抑制了CD73和ADORA2A的表达，而THP-1巨噬细胞中GBP5过表达通过HIF-1α依赖性转录激活增强了CD73表达，并经双荧光素酶报告基因实验证实。CD73过表达反过来升高了cAMP/p-CREB信号并抑制了NLRP3炎症小体活性。GBP5通过NLRP3炎症小体活化加重ALI，同时驱动一个代偿性的HIF-1α-CD73-腺苷-cAMP-CREB反馈环路以限制过度炎症。靶向这一双通路可能为ALI和ARDS提供新的治疗策略。
Abstract
Guanylate-binding protein 5 (GBP5) is an interferon-inducible GTPase that promotes NLRP3 inflammasome activation. However, its role in acute lung injury (ALI) and its relationship with compensatory anti-inflammatory pathways remain poorly defined. Methods: We employed an LPS-induced ALI mouse model with AAV-mediated intratracheal GBP5 knockdown, transcriptomic profiling (RNA-seq), and in vitro studies in THP-1 macrophages. GBP5 overexpression and CD73 overexpression were used to dissect the GBP5-HIF-1α-CD73-adenosine axis. RNA-seq analysis of LPS-induced lung injury revealed upregulation of GBP family members (particularly GBP5) and multiple adenosine metabolism genes. AAV-mediated GBP5 knockdown in male C57BL/6 mice (6-8 weeks, n = 10/group) attenuated LPS-induced lung injury, reduced NLRP3 inflammasome activation (NLRP3, ASC, cleaved caspase-1), and decreased inflammatory cytokine levels (IL-1β, IL-6, TNF-α). In parallel, GBP5 knockdown suppressed CD73 and ADORA2A expression, whereas GBP5 overexpression in THP-1 macrophages enhanced CD73 expression via HIF-1α-dependent transcriptional activation confirmed by dual-luciferase reporter assays. CD73 overexpression in turn elevated cAMP/p-CREB signaling and suppressed NLRP3 inflammasome activity. GBP5 exacerbates ALI through NLRP3 inflammasome activation while simultaneously driving a compensatory HIF-1α-CD73-adenosine-cAMP-CREB feedback loop that restrains excessive inflammation. Targeting this dual pathway may offer novel therapeutic strategies for ALI and ARDS.
如何引用
AMA
Jia Zhang, Linshu Xie, Xinyu Yang, Qianqian Liu, Xiaoju Zhang. GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α-CD73-adenosine Feedback Loop.. Inflammation. 2026; doi:10.1007/s10753-026-02528-0.
APA
Jia Zhang, Linshu Xie, Xinyu Yang, Qianqian Liu, Xiaoju Zhang (2026). GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α-CD73-adenosine Feedback Loop.. Inflammation. https://doi.org/10.1007/s10753-026-02528-0
GB/T 7714
Jia Zhang, Linshu Xie, Xinyu Yang, Qianqian Liu, Xiaoju Zhang. GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α-CD73-adenosine Feedback Loop.[J]. Inflammation, 2026 doi:10.1007/s10753-026-02528-0.
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