Regulation of cytosolic pattern recognition receptor signaling in macrophages

急性炎症反应对宿主防御非常有益，以消除感染并启动炎症反应。 伤口愈合然而，不适当的，不受控制的炎症反应会导致有害的 扩大的炎性疾病谱的病理学。促进炎症的关键途径 炎症反应是炎性小体，它是由NLR的上游传感器组成的信号平台， ALR家族，adaptor ASC和Caspase-1。炎症体激活促进Caspase-1的激活 随后释放白细胞介素（IL）-1b和IL-18，并诱导细胞死亡。 炎性小体通过涉及引发和激活的2步机制激活，但精确的 控制和维持平衡的炎性体反应的调节机制， 体内平衡，仍然知之甚少，但对于开发新的和改进的疗法是关键的。 这项更新申请中概述的研究重点是阐明 我们发现了两种抑制这种反应功能的抑制剂，以抑制炎症，以及这种活性是如何 对预防炎症性疾病很重要。我们发现了PYRIN结构域（PYD）的所有三个成员- 只有蛋白质（POP）家族的小内源性蛋白质，我们证明了其功能， 解决炎症反应。持久性有机污染物最近才在人类中进化出来，但在小鼠和我们身上却没有。 建立了新的转基因小鼠模型，以研究体内巨噬细胞中的持久性有机污染物。第一次融资期间 在此期间，我们发现了这些持久性有机污染物中的每一种抑制炎性小体激活的精确机制， 炎性小体组装水平。我们还发现两个成员有第二个独特的 在调节巨噬细胞的启动中具有炎性体非依赖性作用，这也是调节巨噬细胞启动的第一个关键步骤。 炎性小体激活。我们的主要目标是这个更新的应用程序是描绘精确的机制， 其中POP 2和POP3调节巨噬细胞的炎症引发，采用生物化学、分子和 遗传学研究，重点是I型干扰素（IFN-I）的产生和非典型的NF-kB激活。 因此，持久性有机污染物在几个水平上调节巨噬细胞的炎症反应，这最终阻止了 细胞因子释放因此，剖析这些独特的POP 2和POP3活动将提供新的见解， 这个重要但仍知之甚少的蛋白质家族如何调节关键的先天免疫信号通路， 因此，这对于更好地理解炎性疾病病理学是非常重要的。总的来说， 因此，我们的研究结果将对人类健康产生巨大影响。

Acute inflammatory responses are highly beneficial for host defense to eliminate infections and to initiate wound healing. However, inappropriate, uncontrolled inflammatory responses cause the detrimental pathologies of an expanding spectrum of inflammatory diseases. A key pathway promoting inflammatory responses is the inflammasome, which is a signaling platform composed of an upstream sensor of the NLR or ALR families, the adaptor ASC and Caspase-1. Inflammasome activation promotes activation of Caspase-1 and subsequent release of interleukin (IL)-1b and IL-18 and the induction of pyroptotic cell death. Inflammasomes are activated by a 2-step mechanism involving priming and activation, but the precise regulatory mechanisms that control and maintain a balanced inflammasome response and consequently homeostasis, are still poorly understood, but are key for developing novel and improved therapies. The research outlined in this renewal application is focused on elucidating the molecular mechanism by which two by us discovered inhibitors of this response function to dampen inflammation, and how this activity is important to prevent inflammatory disease. We discovered all three members of the PYRIN domain (PYD)- only protein (POP) family of small endogenous proteins, which we demonstrated to function by inhibiting and resolving inflammatory responses. POPs very recently evolved in humans, but are lacking from mice and we generated novel transgenic mouse models to study POPs in macrophages in vivo. During the 1st funding period, we discovered the precise mechanism by which each of these POPs inhibit inflammasome activation at the level of inflammasome assembly. We also discovered that two members have a second unique inflammasome-independent role in regulating priming of macrophages, which is also the first key step in inflammasome activation. Our main goal for this renewal application is to delineate the precise mechanisms by which POP2 and POP3 regulate inflammatory priming of macrophages, employing biochemical, molecular and genetic studies, focusing on type I interferon (IFN-I) production and non-canonical NF-kB activation. Hence, POPs regulate inflammatory responses of macrophages at several levels, which ultimately prevents cytokine release. Therefore, dissecting these unique POP2 and POP3 activities will provide novel insights into how this important, but still poorly understood protein family regulates key innate immune signaling pathways, which is therefore highly significant for better understanding inflammatory disease pathologies. Collectively, our results will therefore have tremendous implications for human health.