Non-canonical responses to IFNab in the suppression of macrophage immunity

项目摘要： 巨噬细胞和其他骨髓细胞是对感染的先天免疫反应的关键参与者。髓样细胞 发育、募集、激活和杀微生物活性受I型和II型干扰素（IFN γ）调节。 （IFN）。干扰素β和干扰素β在微生物感染过程中同时产生，但具有不同的 一些情况下相反-对骨髓细胞功能的影响。IFN γ激活巨噬细胞的杀微生物活性 并且通常降低宿主对细胞内微生物的易感性。相反，干扰素β抑制骨髓细胞， IFN γ激活并增加宿主对某些细菌的易感性。IFN γ的作用机制 抑制骨髓细胞活化仍然不完全了解。我们先前的研究表明， 触发IFN γ受体IFNGR 1的下调，特别是在骨髓细胞中。此次下调 发生在转录水平上，并且独立于STAT蛋白质，对于其他重要的，“典型的”， 对I型干扰素的反应。我们已经开始研究ifngr 1下调的机制， 鉴定了这一过程的抑制剂，并获得了两种以前没有的特异性宿主蛋白质的证据。 与I型IFN应答相关的蛋白质对于IFNGR下调是重要的。在这一探索性的R21赠款中， 应用，我们提出的实验，以进一步剖析这些蛋白质如何交叉I型干扰素信号 途径，并评估其对巨噬细胞中整体髓样细胞基因表达模式的影响。 静息和IFN β刺激状态。来自这些研究的信息将提供对免疫抑制的深入了解。 IFN β的非典型应答及其对宿主对微生物感染易感性的影响。

Project Summary: Macrophages and other myeloid cells are key players in the innate immune response to infection. Myeloid cell development, recruitment, activation, and microbicidal activity are regulated by type I and II interferons (IFN�� and IFN�). IFN�� and IFN� are concurrently produced during microbial infections but have different - and in some cases opposing - effects on myeloid cell function. IFN� activates microbicidal activity of macrophages and typically reduces host susceptibility to intracellular microbes. Conversely, IFN�� suppresses myeloid cell activation by IFN� and increases host susceptibility to certain bacteria. The mechanisms by which IFN�� suppresses myeloid cell activation remain incompletely understood. Our prior studies showed that IFN�� triggers down regulation of the receptor for IFN�, IFNGR1, specifically in myeloid cells. This down regulation occurs at the transcriptional level and is independent of STAT proteins important for other, "canonical," responses to type I IFNs. We have begun to investigate the mechanisms for ifngr1 down regulation and have identified inhibitors of this process and obtained evidence that two specific host proteins not previously associated with type I IFN responses are important for IFNGR down regulation. In this exploratory R21 grant application we propose experiments to further dissect how these proteins intersect the type I IFN signaling pathway in macrophages and to evaluate their impact on global myeloid cell gene expression patterns in resting and IFN�-stimulated states. Information from these studies will provide insight into immune-suppressive non-canonical responses to IFN�� and their effects on host susceptibility to microbial infections.