Molecular Regulation of Systemic Inflammation

 描述（由申请人提供）脓毒症是高收入国家的第十大死亡原因，发病率稳步上升，由免疫系统对侵入性病原体的过度反应引起。死亡率是复杂的宿主反应的结果，包括初始细胞因子风暴以及继发性免疫抑制。分别通过激活半胱天冬酶-1和半胱天冬酶-11（人类中的半胱天冬酶-4）的经典和非经典炎性体途径对于介导对胞质病原体及其PAMPS（包括LPS）的应答是必不可少的，从而导致焦亡和细胞因子和危险信号的释放。经典途径由胞质PRR（包括NLRP 3）激活。NLRP 3炎性体的组装和信号传导依赖于NLRP 3和衔接子ASC之间的PYRIN结构域（PYD）-PYD相互作用。非经典途径响应于胞质LPS和革兰氏阴性细菌逃离具有焦亡的吞噬体，并使经典NLRP 3炎性体参与细胞因子释放以用于宿主防御。然而，终止缺陷和不受控制的活性导致过度的全身性炎症，并与炎症和免疫疾病有关。NLRP 3的遗传突变导致Cryopyrinopathies（CAPS），这是一种全身性炎症性疾病，可在小鼠中重现。炎性小体颗粒也由MΦ释放并充当危险信号以进一步使炎症持续到旁观者细胞，并且这些颗粒在炎性疾病患者的血清中和细菌感染期间被发现，并被认为是持续和慢性反应的原因。因此，炎症体反应的调节/解决对于维持体内平衡至关重要，但分子机制知之甚少。我们发现了仅PYD蛋白（POP）1，并建立了POP家族的炎性小体抑制剂，这些抑制剂存在于人类中，但缺乏小鼠，其内源性功能尚未阐明。因此，我们开发了一种新的小鼠模型来研究体内POP 1。我们鉴定了POP 1作为全身性炎症疾病期间典型和非典型炎性小体以及旁观者细胞应答的第一关键调节因子，发现了POP 1在人类患者中的脱轨表达，因此本申请的目的是阐明人和小鼠巨噬细胞中和体内的分子机制。我们期望这种炎症体通路调控的未被揭示的分子机制将广泛适用于其他炎症和感染，从而对人类健康产生积极影响。

 DESCRIPTION (provided by applicant) Sepsis is the 10th leading cause of mortality in high-income countries with steadily rising incidence rates, caused by an over-reaction of the immune system to invasive pathogens. Mortality is a consequence of the complex host response with both the initial cytokine storm, as well as secondary immune suppression. Both the canonical and non-canonical inflammasome pathways through activation of caspases-1 and caspase-11 (caspase-4 in humans), respectively, are essential for mediating the responses to cytosolic pathogens and their PAMPS, including LPS, leading to pyroptosis and release of cytokines and danger signals. The canonical pathway is activated by cytosolic PRRs, including NLRP3. Assembly and signaling of the NLRP3 inflammasome is dependent on the PYRIN domain (PYD)-PYD interaction between NLRP3 and the adaptor ASC. The non-canonical pathway responds to cytosolic LPS and Gram-negative bacteria escaping the phagosome with pyroptosis, and engages the canonical NLRP3 inflammasome for cytokine release for host defense. However, defects in termination and uncontrolled activity results in excessive systemic inflammation and is linked to inflammatory and immune diseases. Hereditary mutations in NLRP3 cause Cryopyrinopathies (CAPS), a systemic inflammatory disease, which can be recapitulated in mice. Inflammasome particles are also released by MΦ and act as danger signals to further perpetuate inflammation to bystander cells, and these particles are found in sera in inflammatory disease patients and during bacterial infection and are thought to be responsible for the persistent and chronic responses. Thus, regulation/resolution of inflammasome responses is of utmost importance for maintaining homeostasis, but the molecular mechanisms are poorly understood. We discovered the PYD-only protein (POP)1 and established the POP family of inflammasome inhibitors, which are present in humans, but are lacking from mice and their endogenous functions have not been elucidated. We therefore developed a novel mouse model to study POP1 in vivo. We identified POP1 as a first key regulator for both the canonical and non- canonical inflammasomes as well as the bystander cell response during systemic inflammatory disease, discovered derailed expression of POP1 in human patients, and the objective of this application is therefore to elucidate the molecular mechanism in human and mouse macrophages and in vivo. We expect that the uncovered molecular mechanisms of this inflammasome pathway regulation will be widely applicable to other inflammasomopathies and infections and therefore positively affect human health.