Neutrophil IFN-gamma in host defense and inflammation

 描述（由申请人提供）：IFN-γ是介导宿主对多种细胞内病原体抗性的关键细胞因子。直到最近，人们才普遍认识到淋巴细胞是IFN-γ的唯一来源。我们最近已经确定中性粒细胞是IFN-γ的一种新兴的细胞来源，IFN-γ是介导宿主防御弓形虫和其他细胞内病原体的关键细胞因子。与淋巴样细胞相反，嗜中性粒细胞产生IFN-γ是Toll样受体（TLR）和IL-12非依赖性的，并且与嗜中性粒细胞产生IFN-γ相关的事件尚不清楚。我们还观察到，中性粒细胞在其骨髓小生境中的谱系发育过程中表达IFN-γ，与微生物无关。IFN-γ在嗜中性粒细胞颗粒中积累，并在诱导嗜中性粒细胞脱粒时释放。我们建议建立在这些研究结果，以获得更深入的了解如何调节嗜中性粒细胞衍生的IFN-γ的表达，并调查的生理意义，嗜中性粒细胞衍生的IFN-γ在小鼠和人类模型的弓形虫病。在目标1中，我们将鉴定参与幼稚和刚地弓形虫感染小鼠中IFN-γ产生的中性粒细胞前体，并确定调节人和小鼠中性粒细胞中IFN-γ产生的转录因子。在目标2中，我们将使用携带嗜中性粒细胞特异性IFN-γ缺陷的小鼠来测试嗜中性粒细胞衍生的IFN-γ协调对弓形虫的先天性和适应性免疫应答的假设。这些研究将推进我们对人类和小鼠先天免疫系统如何

 DESCRIPTION (provided by applicant): IFN- is a key cytokine that mediates host resistance to a variety of intracellular pathogen. Until recently, it was largely acknowledged that lymphoid cells are the sole sources for IFN-. We have recently established that neutrophils are an emerging cellular source of IFN-, a key cytokine that mediates host defense to Toxoplasma gondii and other intracellular pathogens. Production of IFN-by neutrophils, in contrast to lymphoid cells, is Toll-like receptor (TLR) and IL-12-independent and the events associated with IFN- production by neutrophils are not understood. We have also observed that neutrophils express IFN-during their lineage development in the bone marrow niche independently of microbes. IFN- accumulates in neutrophilic granules and is released upon induction of neutrophil degranulation. We propose to build upon these findings to gain a deeper understanding of how neutrophil-derived IFN- expression is regulated, and to investigate the physiological significance of neutrophil-derived IFN- in mouse and human models of toxoplasmosis. In Aim 1, we will identify neutrophil precursors involved in IFN- production in naïve and Toxoplasma gondii-infected mice and determine the transcription factors that regulate IFN- production in human and mouse neutrophil. In Aim 2, we will use mice harboring neutrophil-specific IFN- deficiency to test the hypothesis that neutrophil-derived IFN-coordinates innate and adaptive immune responses to Toxoplasma gondii. These studies will advance our understanding of how human and mouse innate immune systems