Davidson Sophia, Crotta Stefania, McCabe Teresa M, Wack Andreas
Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Nat Commun. 2014 May 21;5:3864. doi: 10.1038/ncomms4864.
Influenza symptoms vary from mild disease to death; however, determinants of severity are unclear. Type I interferons (IFNαβ) are recognized as key antiviral cytokines. Here we show that, surprisingly, influenza-infected 129 mice have increased lung damage, morbidity and mortality, yet higher levels of IFNαβ, than C57BL/6 mice. Consistently, IFNα treatment of influenza-infected C57BL/6 mice increases morbidity. IFNαβ receptor deficiency in 129 mice decreases morbidity, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells, and reduces expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes. Depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protects infected 129 mice. Selective lack of IFNαβ signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFNαβ signalling in response to acute influenza infection can result in uncontrolled inflammation and TRAIL-DR5-mediated epithelial cell death, which may explain morbidity and has important implications for treatment of severe disease.
流感症状从轻症到死亡各不相同；然而，严重程度的决定因素尚不清楚。I型干扰素（IFNαβ）被认为是关键的抗病毒细胞因子。在此我们发现，令人惊讶的是，感染流感的129小鼠比C57BL/6小鼠有更严重的肺损伤、发病率和死亡率，但IFNαβ水平却更高。同样，用IFNα治疗感染流感的C57BL/6小鼠会增加发病率。129小鼠中IFNαβ受体缺陷可降低发病率、肺损伤、促炎细胞因子和肺浸润性炎症细胞，并减少肺上皮细胞上死亡诱导受体DR5及其配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）在炎性单核细胞上的表达。清除浆细胞样树突状细胞（PDCA-1+细胞）或阻断TRAIL-DR5相互作用可保护感染的129小鼠。基质细胞中选择性缺乏IFNαβ信号可消除上皮细胞DR5上调和凋亡，降低宿主易感性。因此，对急性流感感染的过度IFNαβ信号传导可导致不受控制的炎症和TRAIL-DR5介导的上皮细胞死亡，这可能解释了发病率，并对重症治疗具有重要意义。
