Influenza A virus (IAV) is among the most common causes of pneumonia-related death worldwide. Pulmonary epithelial cells are the primary target for viral infection and replication and respond by releasing inflammatory mediators that recruit immune cells to mount the host response. Severe lung injury and death during IAV infection result from an exuberant host inflammatory response. The linear ubiquitin assembly complex (LUBAC), composed of SHARPIN, HOIL-1L, and HOIP, is a critical regulator of NF-κB–dependent inflammation. Using mice with lung epithelial–specific deletions of HOIL-1L or HOIP in a model of IAV infection, we provided evidence that, while a reduction in the inflammatory response was beneficial, ablation of the LUBAC-dependent lung epithelial–driven response worsened lung injury and increased mortality. Moreover, we described a mechanism for the upregulation of HOIL-1L in infected and noninfected cells triggered by the activation of type I IFN receptor and mediated by IRF1, which was maladaptive and contributed to hyperinflammation. Thus, we propose that lung epithelial LUBAC acts as a molecular rheostat that could be selectively targeted to modulate the immune response in patients with severe IAV-induced pneumonia.

中文翻译：

---

线性泛素装配复合物可调节流感感染期间肺上皮驱动的反应

甲型流感病毒（IAV）是全球范围内与肺炎相关死亡的最常见原因。肺上皮细胞是病毒感染和复制的主要靶标，并通过释放炎症性介质做出反应，而炎症性介质会募集免疫细胞以引起宿主反应。IAV感染期间严重的肺损伤和死亡是由旺盛的宿主炎症反应导致的。由SHARPIN，HOIL-1L和HOIP组成的线性泛素装配复合物（LUBAC）是NF-κB依赖性炎症的关键调节剂。在IAV感染模型中，使用具有肺上皮特异性HOIL-1L或HOIP缺失的小鼠，我们提供了证据，尽管炎症反应的减少是有益的，但LUBAC依赖性肺上皮驱动反应的消融使肺损伤恶化并增加死亡率。此外，我们描述了由I型IFN受体激活并由IRF1介导的感染和未感染细胞中HOIL-1L上调的机制，这是适应不良的，并导致过度炎症。因此，我们建议肺上皮LUBAC充当分子变阻器，可以有针对性地调节重度IAV诱导的肺炎患者的免疫应答。