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

项目总结： 巨噬细胞和其他髓系细胞是对感染的先天免疫反应中的关键角色。髓系细胞 I型和II型干扰素(干扰素��)调节发育、募集、激活和杀菌活性 和干扰素�)。干扰素��和干扰素�在微生物感染过程中同时产生，但具有不同的-和 一些病例对髓系细胞功能有相反的影响。干扰素�激活巨噬细胞的杀菌活性 通常会降低宿主对细胞内微生物的敏感性。相反，干扰素��抑制髓系细胞 由干扰素�激活，并增加宿主对某些细菌的敏感性。干扰素��的作用机制 抑制髓系细胞激活的机制仍不完全清楚。我们先前的研究表明，干扰素�� 触发干扰素�受体的下调，特别是在髓系细胞中。这一降级规定 发生在转录水平，独立于其他重要的STAT蛋白，“规范的， 对I型IFN的反应。我们已经开始研究ifngr1下调的机制，并已经 确定了这一过程的抑制物，并获得了两种特定的宿主蛋白以前没有 与I型相关的干扰素反应对IFNGR下调很重要。在这项试探性的R21拨款中 应用我们提出的实验，以进一步剖析这些蛋白质如何与I型干扰素信号相交 在巨噬细胞中的途径，并评价其对全球髓系细胞基因表达模式的影响。 静息状态和干扰素�刺激状态。来自这些研究的信息将提供对免疫抑制的洞察 干扰素��的非典型反应及其对宿主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.