Expression of suppressor of cytokine signaling 1 (SOCS1) impairs viral clearance and exacerbates lung injury during influenza infection.
Expression of suppressor of cytokine signaling 1 (SOCS1) impairs viral clearance and exacerbates lung injury during influenza infection.
复制标题
抑制细胞因子信号传导1（SOCS1）的表达会损害病毒清除率，并加剧流感感染期间的肺损伤。
DOI：
10.1371/journal.ppat.1004560
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发表时间：
2014-12
期刊：
影响因子：
6.7
通讯作者：
Metzger DW
中科院分区：
文献类型：
--
作者：
Sun K;Salmon S;Yajjala VK;Bauer C;Metzger DW
细胞因子信号转导抑制因子（SOCS）蛋白是细胞因子信号转导的可诱导反馈抑制剂。SOCS 1 −/−小鼠在出生后三周内死于IFN-γ诱导的过度炎症。由于已经确定IFN-γ可以保护免受流感感染，因此我们产生了SOCS 1 −/−IFN-γ−/−小鼠以确定SOCS 1是否调节体内抗病毒免疫。在这里，我们发现SOCS 1 −/−IFN-γ−/−小鼠对流感感染的抵抗力显著增强，与IFN-γ−/−或WT动物相比，病毒清除率提高，急性肺损伤减轻，因此存活率增加。SOCS 1-/-IFN-γ-/-小鼠的病毒清除增强与急性感染期间适应性免疫反应的快速启动相一致，而其肺损伤的减轻与感染消退阶段炎症细胞浸润的减少有关。我们进一步确定了SOCS 1缺陷型T细胞对抗病毒免疫的贡献。SOCS 1 −/−IFN-γ−/−小鼠的抗CD 4抗体治疗对其增强的流感感染抵抗力没有显著影响，而SOCS 1 −/−IFN-γ−/−小鼠的CD 8+脾细胞足以拯救RAG 1 −/−动物免于致命感染。令人惊讶的是，尽管它们的病毒负荷显著降低，但用SOCS 1 −/−IFN-γ−/−适应性免疫细胞重建的RAG 1 −/−小鼠未能改善流感诱导的肺损伤。总之，在没有IFN-γ的情况下，胞质蛋白SOCS 1不仅抑制适应性抗病毒免疫应答，而且还加剧炎性肺损伤。重要的是，SOCS 1的这些有害作用是通过离散的细胞群传递的。具体而言，虽然SOCS 1在适应性免疫细胞中的表达足以抑制抗病毒免疫，但先天性/基质细胞中的SOCS 1是加重肺损伤的原因。细胞因子在流感感染期间调节保护性免疫和有害炎症之间的平衡至关重要。细胞因子信号转导抑制因子（SOCS）蛋白是细胞因子信号转导的可诱导反馈抑制剂。使用基因缺陷和感染性动物模型，我们确定了SOCS 1如何调节针对流感感染的免疫防御。我们发现，细胞内蛋白SOCS 1不仅抑制适应性抗病毒免疫反应，但也加剧了炎症性肺损伤。SOCS 1的这些有害作用通过离散的细胞群传递。具体而言，虽然SOCS 1在适应性免疫细胞中的表达足以抑制抗病毒免疫，但先天性/基质细胞中的SOCS 1是加重肺损伤的原因。据我们所知，没有报道显示SOCS 1在流感感染过程中的调节作用，重要的是，没有证据直接将SOCS 1与其他传染病模型中的过度炎症联系起来。如本研究所揭示的，SOCS 1的独特和非竞争性有害作用使其成为设计对抗流感感染的有效免疫疗法的有吸引力的靶标。
Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1−/− mice die within three weeks postnatally due to IFN-γ-induced hyperinflammation. Since it is well established that IFN-γ is dispensable for protection against influenza infection, we generated SOCS1−/−IFN-γ−/− mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1−/−IFN-γ−/− mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-γ−/− or WT animals. Enhanced viral clearance in SOCS1−/−IFN-γ−/− mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1−/−IFN-γ−/− mice had no significant effect on their enhanced resistance to influenza infection, while CD8+ splenocytes from SOCS1−/−IFN-γ−/− mice were sufficient to rescue RAG1−/− animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1−/− mice reconstituted with SOCS1−/−IFN-γ−/− adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-γ, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury. Cytokines are critical in regulating the balance between protective immunity and detrimental inflammation during influenza infection. Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. Using gene-deficient and infectious animal models, we determined how SOCS1 regulates immune defense against influenza infection. We show that the intracellular protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. These detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury. To our knowledge, there is no report showing the regulatory role of SOCS1 during the course of influenza infection, and importantly, no evidence directly linking SOCS1 with excessive inflammation in other infectious disease models. The distinct and non-competing detrimental roles of SOCS1, as revealed in this study, make it an appealing target in the design of effective immunotherapies for combating influenza infection.
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