铁过载激活Gasdermin D放大过敏性气道炎症

文献信息

中文摘要

过敏性气道疾病，包括哮喘和过敏性鼻炎，代表着迅速增长的全球健康危机。相当比例的患者对靶向经典2型辅助性T细胞（Th2）炎症的标准生物制剂治疗反应不足。当前呼吸研究正在经历根本性的概念转变，从孤立的免疫细胞网络扩展到研究复杂的代谢重编程和程序性细胞死亡。这篇综合性综述旨在阐明铁稳态失衡作为气道病理关键驱动因素的新兴作用及其与非典型结构蛋白切割的特异性相互作用。虽然传统模型将Gasdermin D（GSDMD）视为经典细胞焦亡中被炎症蛋白酶（caspases）激活的终末执行者，但近期突破揭示了一种由铁过载和严重氧化应激直接驱动的新型、不依赖蛋白酶的GSDMD切割机制。这一非典型的铁-GSDMD轴充当类铁死亡脂质过氧化与经典细胞焦亡之间的关键交汇节点。由此产生的GSDMD孔形成导致上皮物理屏障的大规模破坏以及危险相关分子模式（DAMPs）、IL-1β和IL-18的外化。这一过程以指数方式放大局部组织炎症，驱动经典2型反应和非典型中性粒细胞性炎症，最终导致慢性、不可逆的气道重塑。这一新型铁-GSDMD轴从根本上改变了我们对呼吸免疫学的理解，并为难治性临床表现提供了令人信服的机制解释。开发结合主动免疫调节、通过铁调节进行代谢纠正以及屏障修复的治疗干预措施，为治疗严重且治疗抵抗的过敏性气道疾病提供了变革性的临床范式。

英文摘要

Allergic airway diseases, including asthma and allergic rhinitis, represent a rapidly growing global health crisis. A significant proportion of patients exhibit inadequate responses to standard biological therapies targeting classical T helper Type 2 (Th2) inflammation. Current respiratory research is undergoing a fundamental conceptual transformation, expanding beyond isolated immune cell networks to investigate complex metabolic reprogramming and programmed cell death. This comprehensive review aims to elucidate the emerging role of iron homeostasis imbalance as a critical driver of airway pathology and its specific interaction with atypical structural protein cleavage. While traditional models identify Gasdermin D (GSDMD) as a terminal executioner activated by inflammatory proteases (caspases) in canonical pyroptosis, recent breakthroughs reveal a novel, protease-independent GSDMD cleavage mechanism driven directly by iron overload and severe oxidative stress. This atypical iron-GSDMD axis acts as a crucial intersection node between ferroptosis-like lipid peroxidation and classical pyroptosis. The resulting GSDMD pore formation causes massive physical epithelial barrier destruction and the externalization of danger-associated molecular patterns (DAMPs), IL-1β, and IL-18. This process exponentially amplifies local tissue inflammation, driving both classical Type 2 responses and atypical neutrophilic inflammation, ultimately leading to chronic, irreversible airway remodeling. The novel iron-GSDMD axis fundamentally transforms our understanding of respiratory immunology and offers a compelling mechanistic explanation for refractory clinical presentations. Developing therapeutic interventions that incorporate active immune regulation, metabolic correction via iron modulation, and barrier restoration provides a transformative clinical paradigm for treating severe and treatment-resistant allergic airway diseases.