Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut.
Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut.
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DOI：
10.3389/fimmu.2017.00459
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发表时间：
2017
影响因子：
7.3
通讯作者：
Boulant S
中科院分区：
文献类型：
--
作者：
Pervolaraki K;Stanifer ML;Münchau S;Renn LA;Albrecht D;Kurzhals S;Senís E;Grimm D;Schröder-Braunstein J;Rabin RL;Boulant S
肠上皮细胞（IECs）不断暴露于共生菌群和病原体的挑战。IECs如何调节其先天免疫反应以维持肠道稳态尚不清楚。干扰素（ifn）是感染过程中产生的细胞因子。虽然I型IFN受体普遍表达，但III型IFN受体仅在上皮细胞上表达。这种上皮特异性强烈表明在上皮表面具有排他功能，但I型和III型ifn在人iec中建立抗病毒先天免疫反应中的相对作用尚未明确定义。在这里，我们使用微型肠道类器官来定义I型和III型ifn保护人类肠道免受病毒感染的功能。我们发现，初生未转化的人IECs在病毒攻击时，在转录水平上调I型和III型IFN的表达，但在上清中仅分泌III型IFN。然而，人类IECs对I型和III型ifn都有反应，通过产生ifn刺激的基因，进而诱导抗病毒状态。通过基因消融I型或III型IFN受体，我们发现IFN可以独立地限制人类iec中的病毒感染。重要的是，我们首次报道了每个IFN建立抗病毒状态的机制差异。与I型IFN相反，III型IFN诱导的抗病毒活性强烈依赖于有丝分裂原激活的蛋白激酶信号通路，这表明III型IFN使用的途径非冗余地参与抗病毒状态。总之，我们证明了人类肠上皮细胞特异性调节其先天免疫反应，倾向于III型ifn介导的信号，这允许有效地保护病原体，而不会产生过度的炎症。我们的研究结果强烈表明，III型IFN构成了人类肠道抗病毒反应的前线。我们认为粘膜表面，特别是胃肠道，已经进化到有利于III型ifn介导的病原体感染反应，因为它允许信号的空间隔离和适度的炎症信号的产生，我们认为这是维持肠道稳态的关键。
Intestinal epithelial cells (IECs) are constantly exposed to commensal flora and pathogen challenges. How IECs regulate their innate immune response to maintain gut homeostasis remains unclear. Interferons (IFNs) are cytokines produced during infections. While type I IFN receptors are ubiquitously expressed, type III IFN receptors are expressed only on epithelial cells. This epithelium specificity strongly suggests exclusive functions at epithelial surfaces, but the relative roles of type I and III IFNs in the establishment of an antiviral innate immune response in human IECs are not clearly defined. Here, we used mini-gut organoids to define the functions of types I and III IFNs to protect the human gut against viral infection. We show that primary non-transformed human IECs, upon viral challenge, upregulate the expression of both type I and type III IFNs at the transcriptional level but only secrete type III IFN in the supernatant. However, human IECs respond to both type I and type III IFNs by producing IFN-stimulated genes that in turn induce an antiviral state. Using genetic ablation of either type I or type III IFN receptors, we show that either IFN can independently restrict virus infection in human IECs. Importantly, we report, for the first time, differences in the mechanisms by which each IFN establishes the antiviral state. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen-activated protein kinases signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. In conclusion, we demonstrate that human intestinal epithelial cells specifically regulate their innate immune response favoring type III IFN-mediated signaling, which allows for efficient protection against pathogens without producing excessive inflammation. Our results strongly suggest that type III IFN constitutes the frontline of antiviral response in the human gut. We propose that mucosal surfaces, particularly the gastrointestinal tract, have evolved to favor type III IFN-mediated response to pathogen infections as it allows for spatial segregation of signaling and moderate production of inflammatory signals which we propose are key to maintain gut homeostasis.