Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection.
Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection.
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DOI：
10.1371/journal.ppat.1005338
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发表时间：
2015-12
期刊：
影响因子：
6.7
通讯作者：
Kunkel SL
中科院分区：
文献类型：
--
作者：
Kroetz DN;Allen RM;Schaller MA;Cavallaro C;Ito T;Kunkel SL
甲型流感病毒(IAV)是一种空气传播的病原体，每年都会导致严重的发病率和死亡率。巨噬细胞(Mϕ)是第一个在肺部遇到病毒粒子的免疫群体，需要它们来控制感染。在本研究中，我们探索了细胞因子信号通过染色质的表观遗传修饰来调节M-ϕ的表型和功能的机制。我们发现，I型干扰素能有效上调小鼠和人Mϕ中赖氨酸甲基转移酶SetDb2的表达，进而调节Mϕ介导的免疫应答。在抑制JAK-STAT信号级联后，干扰素-I对SetDB2的诱导作用明显减弱，染色质免疫沉淀显示STAT1和干扰素调节因子7都结合在转录起始点的上游以诱导表达。SetDB2 LacZ报告小鼠的产生揭示了IAV感染导致髓系细胞中SetDB2的系统性上调。在肺组织中，肺泡M-ϕ表达最强，感染后第4天仍有70%以上的LacZ阳性表达。在体内沉默Mϕ中的SetDB2活性可提高致死性IAV感染的存活率。增强的宿主保护与增强的抗病毒反应和较少的呼吸道阻塞相关。通过三甲基化H3K9，SetDB2沉默了Mx1和ISG15的转录，这是抑制IAV复制的抗病毒效应物。因此，基因敲除小鼠在感染后第8天病毒载量减少与肺部ISG15和Mx1转录增加有关。此外，SetDB2还抑制了大量其他具有促炎或免疫调节功能的基因的表达。这包括CCL2，一种通过CCR2发出信号以调节单核细胞向感染部位募集的趋化因子。一贯地，基因敲除的小鼠在IAV感染时产生更多的CCL2，这与肺部炎症单核细胞和肺泡Mϕ的数量增加2倍相关。最后，Mϕ表达的SetDB2在体外抑制了CD4+T细胞产生IL-2、IL-10和干扰素-γ，并抑制了感染IAV的肺组织的增殖。总而言之，这些发现确认SetDB2是急性呼吸道病毒感染中免疫系统的一种新的调节器。IAV引起季节性流行，每年导致严重的发病率和死亡率。较少出现新的病毒株，并导致全球范围内更大规模的疫情爆发。在2009年的上一次大流行中，估计有30万人死于IAV感染或继发性并发症。由于病毒进化迅速，每年都必须开发一种新的疫苗。由于疫苗的有效性可能有很大的变数，因此确定其他治疗靶点对于治疗儿童、老年人和免疫功能低下等高危人群的严重疾病很有吸引力。在本研究中，我们发现在Mϕ中，SetDb2蛋白通过表观遗传机制调节对新城疫病毒的免疫应答。抑制SetDB2活性有利于宿主保护，因为增强了抗病毒反应，这与加速病毒清除和减少对肺部的损害有关。因此，靶向SetDB2可能是一种有效的治疗策略，用于治疗由IAV引起的严重肺部疾病，以及可能引发强劲干扰素-I产生的其他病毒病原体。
Influenza A virus (IAV) is an airborne pathogen that causes significant morbidity and mortality each year. Macrophages (Mϕ) are the first immune population to encounter IAV virions in the lungs and are required to control infection. In the present study, we explored the mechanism by which cytokine signaling regulates the phenotype and function of Mϕ via epigenetic modification of chromatin. We have found that type I interferon (IFN-I) potently upregulates the lysine methyltransferase Setdb2 in murine and human Mϕ, and in turn Setdb2 regulates Mϕ-mediated immunity in response to IAV. The induction of Setdb2 by IFN-I was significantly impaired upon inhibition of the JAK-STAT signaling cascade, and chromatin immunoprecipitation revealed that both STAT1 and interferon regulatory factor 7 bind upstream of the transcription start site to induce expression. The generation of Setdb2 LacZ reporter mice revealed that IAV infection results in systemic upregulation of Setdb2 in myeloid cells. In the lungs, alveolar Mϕ expressed the highest level of Setdb2, with greater than 70% lacZ positive on day 4 post-infection. Silencing Setdb2 activity in Mϕ in vivo enhanced survival in lethal IAV infection. Enhanced host protection correlated with an amplified antiviral response and less obstruction to the airways. By tri-methylating H3K9, Setdb2 silenced the transcription of Mx1 and Isg15, antiviral effectors that inhibit IAV replication. Accordingly, a reduced viral load in knockout mice on day 8 post-infection was linked to elevated Isg15 and Mx1 transcript in the lungs. In addition, Setdb2 suppressed the expression of a large number of other genes with proinflammatory or immunomodulatory function. This included Ccl2, a chemokine that signals through CCR2 to regulate monocyte recruitment to infectious sites. Consistently, knockout mice produced more CCL2 upon IAV infection and this correlated with a 2-fold increase in the number of inflammatory monocytes and alveolar Mϕ in the lungs. Finally, Setdb2 expression by Mϕ suppressed IL-2, IL-10, and IFN-γ production by CD4+ T cells in vitro, as well as proliferation in IAV-infected lungs. Collectively, these findings identify Setdb2 as a novel regulator of the immune system in acute respiratory viral infection. IAV causes seasonal epidemics that result in significant morbidity and mortality annually. Less frequently, novel viral strains emerge and are responsible for much larger outbreaks around the globe. In the last pandemic in 2009, an estimated 300,000 people died from IAV infection or secondary complications. Since the virus rapidly evolves, a new vaccine must be developed each year. Since vaccine effectiveness can be highly variable, identifying other therapeutic targets is appealing for the treatment of severe disease in high-risk individuals such as young children, the elderly, and immunocompromised individuals. In this study, we found that the protein Setdb2 regulates the immune response to IAV via an epigenetic mechanism in Mϕ. Inhibition of Setdb2 activity was beneficial for host protection due to an amplified antiviral response, which correlated with accelerated viral clearance and less damage to the lungs. Therefore, targeting Setdb2 may be a powerful therapeutic strategy for treating severe pulmonary disease caused by IAV and potentially other viral pathogens that trigger robust IFN-I production.