Mechanism of Nlrp3 inflammasome activation by mitochondrial dysfunction

线粒体功能障碍激活Nlrp3炎症小体的机制

基本信息

批准号：
8773574
负责人：
SUZANNE L. CASSEL
金额：
$ 37.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773574
关键词：
Adaptor Signaling Protein Agonist Antibiotics Apoptosis Apoptotic Atherosclerosis Autoimmune Process Binding Candida albicans Cardiolipins Caspase Caspase-1 Cell Death Complex Cytosol Data Development Disease Docking Family member Generations Gout Health Immune response Induction of Apoptosis Infection Inflammatory Interleukin-18 Invaded Laboratories Lead Leucine-Rich Repeat Ligands Lighting Linezolid Link Lipids Location Malignant Neoplasms Membrane Membrane Potentials Metabolic Mitochondria Molecular Movement Multiprotein Complexes NADPH Oxidase Nature Non-Insulin-Dependent Diabetes Mellitus Nucleotides Outcome Outer Mitochondrial Membrane Pathologic Pathway interactions Patients Pattern Reactive Oxygen Species Recruitment Activity Role Signal Transduction Site Source Staphylococcus aureus Stimulus Syndrome Therapeutic Intervention caspase-3 caspase-7 caspase-8 caspase-9 chemical property cytochrome c cytokine fight against improved influenzavirus macrophage mitochondrial dysfunction mitochondrial membrane novel oxidation pathogen physical property response secretion process tumor

项目摘要

DESCRIPTION (provided by applicant): The Nlrp3 inflammasome has been linked to both protective and pathologic immune responses. Its appropriate activation triggers the innate immune response to invading pathogens including influenza virus, Staphylococcus aureus and Candida albicans and its excessive response underlies the autoinflammatory syndromes CAPS (cryopyrin associated periodic syndromes). The Nlrp3 inflammasome is also triggered by abnormal metabolic conditions that lead to the development of common debilitating disorders such as gout, type II diabetes mellitus and atherosclerosis. We have identified a novel step in the pathway by which the Nlrp3 inflammasome is activated that reveals a previously unrecognized overlap with the activation of extrinsic apoptotic pathways. Preliminary studies in our lab show that similar to these apoptotic pathways Nlrp3 inflammasome activation induces mitochondrial dysfunction as demonstrated by a loss of the normal negative potential within the mitochondria. During apoptosis this loss of mitochondrial membrane potential is associated with the translocation of the mitochondrial lipid cardiolipin from its location on the inner mitochondril membrane to the outer membrane. This movement is accompanied by oxidation of cardiolipin and the release of its binding partner, cytochrome c, to the intermembrane space. Cardiolipin on the outer mitochondrial membrane recruits and binds caspase-8 that in turn drives the generation of an outer mitochondrial membrane pore through which cytochrome c, loose from its tether to cardiolipin, crosses to the cytosol and triggers immunologically silent cell death by apoptosis. We now show this requirement for and ability to bind mitochondrial cardiolipin is shared by Nlrp3, previously shown to migrate to the mitochondria during activation. Additionally, the loss of mitochondrial membrane potential, a defining step in apoptosis, is also required for Nlrp3 inflammasome activation. In this proposal we specifically dissect the role of cardiolipin in Nlrp3 activation and determine to what extent Nlrp3 inflammasome activation mirrors apoptosis. These studies will determine the point of divergence of these two pathways, important not only to advance our understanding of this vital inflammatory pathway but also because once identified this switch between pathways may prove to be a target for therapeutic intervention. Manipulation of these pathways is attractive not only for modifying Nlrp3 responses but also for the potential to switch from the apoptotic pathway to an inflammatory one as could be of benefit in the setting of malignancy or covert infections.

描述（由申请人提供）：NLRP3炎性体与保护性和病理免疫反应有关。其适当的激活触发了对包括流感病毒，金黄色葡萄球菌和白色念珠菌在内的入侵病原体的先天免疫反应，其过度反应构成了自发性综合征帽（冷冻蛋白相关的周期性综合征）。 NLRP3炎性体也是由异常的代谢疾病引起的，这些疾病会导致常见的衰弱疾病的发展，例如痛风，II型糖尿病和动脉粥样硬化。我们已经确定了该途径中的新一步，该途径通过该途径激活了NLRP3炎症体，该途径揭示了先前未被认为与外部凋亡途径的激活的重叠。在我们的实验室中，初步研究表明，与这些凋亡途径NLRP3炎性体激活相似，会诱导线粒体功能障碍，如线粒体内正常负电位的丧失所证明。在凋亡过程中，线粒体膜电位的丧失与线粒体脂质心磷脂从其位置的线粒体内部线粒体膜到外膜的位置有关。这种运动伴随着心脂蛋白的氧化及其结合伴侣细胞色素C与膜间空间的释放。在外部线粒体膜新兵上的Cardiolipin并结合caspase-8，caspase-8又驱动了外部线粒体膜孔的产生，细胞色素c通过该孔，从其系带到心脏蛋白，从其延伸到心脏蛋白，从凋亡。现在，我们表明了对线粒体心脂蛋白结合的需求和能力，由NLRP3共享，以前显示在激活过程中迁移到线粒体。此外，NLRP3炎性体激活也需要线粒体膜电位的丧失，这是凋亡的决定性步骤。在此提案中，我们专门剖析了心磷脂在NLRP3激活中的作用，并确定NLRP3炎性体激活在多大程度上反映了凋亡。这些研究将确定这两种途径的差异点，这不仅要促进我们对这一重要炎症途径的理解，而且还因为一旦确定了这种途径之间的这种切换，可能被证明是治疗干预的目标。对这些途径的操纵不仅对于修改NLRP3响应，而且对于从凋亡途径转变为炎症途径的可能性可能会受益，这在恶性或秘密感染的情况下可能有益。