Molecular Regulation of Systemic Inflammation

 说明(申请人提供)脓毒症是高收入国家第十大致死原因，发病率稳步上升，原因是免疫系统对侵袭性病原体反应过度。死亡率是复杂的宿主反应的结果，既有最初的细胞因子风暴，也有次级免疫抑制。分别通过激活caspase-1和caspase-11(在人类中为caspase-4)的典型和非典型炎症体通路，在介导对胞浆病原体及其PAMP(包括内毒素)的反应中是必不可少的，从而导致上睑下垂、细胞因子和危险信号的释放。经典途径由胞质PRRs激活，包括NLRP3。NLRP3炎症体的组装和信号传递依赖于NLRP3与接头ASC之间的吡咯域(PYD)-PYD相互作用。非正则途径对胞液中的内毒素和革兰氏阴性菌逃离吞噬小体并伴有下垂作出反应，并与典型的NLRP3炎性小体接触以释放细胞因子进行宿主防御。然而，终末缺陷和不受控制的活动会导致过度的全身炎症，并与炎症性和免疫性疾病有关。NLRP3的遗传突变会导致冰冻疾病(CAPS)，这是一种全身性炎症性疾病，可以在小鼠身上重复出现。炎症体颗粒也由MΦ释放，作为危险信号进一步延长旁观者细胞的炎症，这些颗粒在炎症性疾病患者和细菌感染期间的血清中发现，被认为是持续和慢性反应的原因。因此，调节/化解炎症体反应对于维持体内平衡至关重要，但其分子机制却知之甚少。我们发现了PYD-Only Protein(POP)1，并建立了炎症小体抑制因子的POP家族，该家族存在于人类中，但在小鼠中缺乏，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POP1在体内的作用。我们确定POP1是全身炎性疾病中典型和非典型炎症体以及旁观者细胞反应的第一个关键调节因子，在人类患者中发现了POP1的脱轨表达，因此这一应用的目的是阐明POP1在人和小鼠巨噬细胞中以及体内的分子机制。我们期望这一炎症体途径调控的分子机制将广泛应用于其他炎症性疾病和感染，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.