Scholarlink

<p>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, <i>n</i> = 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α–CD73–adenosine Feedback Loop

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月23日

查看全文
  • Jia Zhang,
  • Linshu Xie,
  • Xinyu Yang,
  • Qianqian Liu,
  • Xiaoju Zhang

摘要

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.