Ma Linlin, Zhang Peng, Li Xingqiong, Sun Baihe, Li Yuhuan, Jiang Jiandong
Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
iScience. 2025 Feb 26;28(3):112116. doi: 10.1016/j.isci.2025.112116. eCollection 2025 Mar 21.
Influenza A virus (IAV) remains a global health threat, with severe cases causing high morbidity and mortality. Type I interferons (IFN-α/β) are crucial for early innate immunity to IAV but can drive immunopathology. This study investigates the role of heme oxygenase-1 (HO-1), a stress-responsive protein with anti-inflammatory properties, in modulating the immune response to IAV. Lung-tropic adeno-associated virus (AAV)-mediated HO-1 overexpression reduces lung damage by limiting immune cells infiltration, including plasmacytoid dendritic cells and classical monocytes, while promoting regulatory T cells (Tregs) and nonclassical monocytes. Additionally, HO-1 increases macrophage populations, enhancing antiviral responses via IFN pathways. Consistent with this, HO-1 knockout mice experience more severe infections, and HO-1 recruit inhibited IAV replication and alleviated pulmonary inflammation. In addition, compared with wide-type, the catalytically inactive mutation (H25A) impairs HO-1's anti-inflammatory function. These findings underscore HO-1's critical role in balancing antiviral immunity and inflammation, positioning it as a potential therapeutic target for severe influenza.
甲型流感病毒（IAV）仍然是全球健康的一大威胁，严重病例会导致高发病率和高死亡率。I型干扰素（IFN-α/β）对IAV的早期固有免疫至关重要，但也会引发免疫病理学问题。本研究调查了具有抗炎特性的应激反应蛋白血红素加氧酶-1（HO-1）在调节对IAV免疫反应中的作用。肺靶向腺相关病毒（AAV）介导的HO-1过表达通过限制免疫细胞浸润（包括浆细胞样树突状细胞和经典单核细胞）来减少肺损伤，同时促进调节性T细胞（Tregs）和非经典单核细胞的生成。此外，HO-1增加巨噬细胞数量，通过IFN途径增强抗病毒反应。与此一致的是，HO-1基因敲除小鼠会经历更严重的感染，HO-1的募集抑制了IAV复制并减轻了肺部炎症。此外，与野生型相比，催化失活突变（H25A）损害了HO-1的抗炎功能。这些发现强调了HO-1在平衡抗病毒免疫和炎症方面的关键作用，使其成为重症流感潜在的治疗靶点。
