Neutrophil IFN-gamma in host defense and inflammation

 描述(申请人提供)：干扰素-是一种关键的细胞因子，介导宿主对多种细胞内病原体的抵抗。直到最近，人们还普遍认为淋巴样细胞是干扰素-的唯一来源。我们最近发现，中性粒细胞是干扰素-的一个新的细胞来源，干扰素-DNA是一种关键的细胞因子，介导宿主对弓形虫和其他细胞内病原体的防御。与淋巴细胞不同，中性粒细胞产生干扰素-是不依赖于Toll样受体和IL-12的，与中性粒细胞产生干扰素-相关的事件尚不清楚。我们还观察到，中性粒细胞在其骨髓微环境中的谱系发育过程中独立于微生物而表达干扰素-。干扰素-聚集在中性粒细胞中，并在诱导中性粒细胞脱颗粒时释放。我们建议在这些发现的基础上，更深入地了解中性粒细胞来源的干扰素-的表达是如何调节的，并探讨中性粒细胞来源的干扰素-在弓形虫病小鼠和人类模型中的生理学意义。在目标1中，我们将确定在幼稚和弓形虫感染的小鼠中参与干扰素-产生的中性粒细胞前体，并确定调节人和鼠中性粒细胞产生干扰素-的转录因子。在目标2中，我们将使用具有中性粒细胞特异性干扰素-缺陷的小鼠来验证中性粒细胞来源的干扰素-协调弓形虫的先天和获得性免疫反应的假设。这些研究将促进我们对人类和小鼠的先天免疫系统如何

 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