Soluble, but not transmembrane, TNF-α is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology.
Soluble, but not transmembrane, TNF-α is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology.
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DOI：
10.4049/jimmunol.1302729
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Enelow RI
中科院分区：
文献类型：
--
作者：
DeBerge MP;Ely KH;Enelow RI
TNF-α是一种多效性细胞因子，在流感病毒感染过程中具有促炎和抗炎双重作用。TNF-α首先表达为跨膜（TNF-α）蛋白，经蛋白水解处理后释放出可溶性（溶胶）形式。memTNF-α和solTNF-α已显示在几种疾病模型中发挥不同的组织保护或病理作用。然而，memTNF-α或solTNF-α在流感感染后调节肺免疫病理学中的相对作用尚不清楚。因此，我们在仅表达不可切割的memTNF-α或完全缺乏TNF-α的小鼠中进行鼻内流感感染，并检查结果。我们发现，solTNF-α，而不是memTNF-α，是限制免疫反应的大小和损伤程度所必需的。在不存在solTNF-α的情况下，CD 8 + T细胞应答显著增加，包括病毒特异性CD 8 + T细胞，这部分是由于对活化诱导的细胞死亡的抗性增加。我们发现，solTNF-α主要通过TNF受体1（TNFR 1）介导这些免疫调节作用，因为TNFR 1缺乏而TNFR 2缺乏的小鼠表现出与缺乏solTNF-α的小鼠相似的免疫应答失调和损伤加重。我们还发现，在感染早期需要solTNF-α表达来调节CD 8 + T细胞应答的幅度，这表明早期炎症事件对于效应期的调节至关重要。总之，这些发现表明，memTNF-α的加工释放solTNF-α是流感感染期间调节免疫应答的关键事件。
TNF-α is a pleotropic cytokine, which has both proinflammatory and anti-inflammatory functions during influenza infection. TNF-α is first expressed as a transmembrane (mem) protein that is proteolytically processed to release a soluble (sol) form. memTNF-α and solTNF-α have been shown to exert distinct tissue-protective or -pathologic effects in several disease models. However, the relative contributions of memTNF-α or solTNF-α in regulating pulmonary immunopathology following influenza infection are unclear. Therefore, we performed intranasal influenza infection in mice exclusively expressing non-cleavable memTNF-α or lacking TNF-α entirely and examined the outcomes. We found that solTNF-α, but not memTNF-α, was required to limit the size of the immune response and the extent of injury. In the absence of solTNF-α, there was a significant increase in the CD8+ T-cell response, including virus-specific CD8+ T-cells, which was due in part to an increased resistance to activation-induced cell death. We found that solTNF-α mediates these immunoregulatory effects primarily through TNF receptor 1 (TNFR1), since mice deficient in TNFR1, but not TNFR2, exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking solTNF-α. We also found that solTNF-α expression was required early during infection to regulate the magnitude of the CD8+ T-cell response indicating that early inflammatory events are critical for the regulation of the effector phase. Taken together, these findings suggest that processing of memTNF-α to release solTNF-α is a critical event regulating the immune response during influenza infection.
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影响因子：
8
作者：
通讯作者：
--
DOI：
10.1084/jem.20101850
发表时间：
2011-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
64.8
作者：
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