Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection.
Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection.
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DOI：
10.1371/journal.ppat.1004134
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Nicholson SE
中科院分区：
文献类型：
--
作者：
Kedzierski L;Linossi EM;Kolesnik TB;Day EB;Bird NL;Kile BT;Belz GT;Metcalf D;Nicola NA;Kedzierska K;Nicholson SE
细胞因子信号抑制因子（SOCS）蛋白是先天免疫和适应性免疫的关键调节因子。尽管SOCS4在造血系统中广泛表达，但尚未发现其生物学作用。我们证明，缺乏功能性SOCS4蛋白的小鼠迅速死于致病性H1N1流感病毒（PR8）的感染，并且对致病性较低的H3N2 （X31）菌株的感染高度敏感。在缺乏socs4的动物中，这导致体重大幅下降，肺部促炎细胞因子和趋化因子产生失调，病毒清除延迟。这与流感特异性CD8 T细胞到感染部位的运输受损有关，并与T细胞受体激活缺陷有关。这些结果表明，SOCS4是抗病毒免疫的关键调节因子。细胞因子信号蛋白的抑制因子是免疫的关键调节因子。迄今为止，尽管SOCS4在免疫系统细胞中广泛表达，但尚未发现其生物学作用。鉴于其他SOCS蛋白在控制免疫应答中的重要作用，我们培育了SOCS4突变小鼠，并利用小鼠流感感染模型研究了SOCS4的生物学功能。我们证明，缺乏SOCS4的小鼠很快就会死于致病性H1N1流感病毒的感染，并且对致病性较低的H3N2株的感染高度敏感。这是首次在socs4缺陷小鼠中证明功能性表型。我们的研究表明，在socs4缺陷的动物中，肺部的促炎细胞因子和趋化因子产生失调，病毒清除延迟。这与病毒特异性CD8 T细胞到感染部位的运输受损有关，并与T细胞受体激活缺陷有关。这些结果表明，SOCS4是抗病毒免疫的关键调节因子。考虑到当前流感大流行暴发的气候，了解流感炎症反应的调控尤为重要。
Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity. The suppressor of cytokine signaling proteins are key regulators of immunity. As yet there is no described biological role for SOCS4, despite its broad expression in cells of the immune system. Given the important role of other SOCS proteins in controlling the immune response, we have generated SOCS4-mutant mice and used a mouse influenza infection model to investigate the biological function of SOCS4. We demonstrate that mice lacking SOCS4 rapidly succumb to infection with a pathogenic H1N1 influenza virus and are hypersusceptible to infection with the less virulent H3N2 strain. This is the first demonstration of a functional phenotype in SOCS4-deficient mice. Our study reveals that in SOCS4-deficient animals, there is a dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This is associated with impaired trafficking of virus-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity. Understanding the regulation of the inflammatory response to influenza is particularly relevant given the current climate concerning pandemic influenza outbreaks.
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