Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons
Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons
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DOI：
10.1016/j.immuni.2019.07.007
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发表时间：
2019-09-17
期刊：
影响因子：
32.4
通讯作者：
Savan, Ram
中科院分区：
文献类型：
--
作者：
Forero, Adriana;Ozarkar, Snehal;Savan, Ram
I型和III型干扰素（IFN）激活类似的下游信号级联，但与I型IFN不同，III型IFN（IFN λ）在体内不引起强烈的炎症反应。在这里，我们研究了这种差异背后的分子机制。I型和III型干扰素在干扰素刺激的基因表达和促炎反应中显示动力学差异，I型干扰素优先刺激转录因子IRF 1的表达。III型IFN未能诱导IRF 1表达，因为低IFN λ受体丰度和上皮细胞上的STAT 1活化不足，因此不能活化IRF 1促炎基因程序。相反，IFN λ刺激优先诱导涉及组织修复的因子。我们的研究结果表明，IFN受体区室化和丰度赋予劳动力的时空分工，III型IFN控制病毒在感染部位的传播，同时限制组织损伤; I型IFN的炎症反应的瞬时诱导招募免疫效应子，以促进保护性免疫。
Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFN lambda) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type I and III IFNs displayed kinetic differences in expression of IFN-stimulated genes and proinflammatory responses, with type I IFNs preferentially stimulating expression of the transcription factor IRF1. Type III IFNs failed to induce IRF1 expression because of low IFN lambda receptor abundance and insufficient STAT1 activation on epithelial cells and thus did not activate the IRF1 proinflammatory gene program. Rather, IFN lambda stimulation preferentially induced factors implicated in tissue repair. Our findings suggest that IFN receptor compartmentalization and abundance confer a spatiotemporal division of labor where type III IFNs control viral spread at the site of the infection while restricting tissue damage; the transient induction of inflammatory responses by type I IFNs recruits immune effectors to promote protective immunity.