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Mechanisms of NIrp3 inflammasome activation by mitochondrial dysfunction

线粒体功能障碍激活 NIrp3 炎症小体的机制

基本信息

批准号：
9392881
负责人：
SUZANNE L. CASSEL
金额：
$ 43.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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/9392881
关键词：
Adaptor Signaling Protein Agonist Antibiotics Apoptosis Apoptotic Atherosclerosis Autoimmune Process Binding CASP1 gene CASP3 gene CASP7 gene CASP8 gene CASP9 gene Candida albicans Cardiolipins Caspase Cell Death Complex Cytosol Data Development Disease Docking Family member Generations Gout Immune response Immunologics Induction of Apoptosis Infection Inflammasome Inflammatory Innate Immune Response Interleukin-1 beta 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 Outer Mitochondrial Membrane Pathologic Pathway interactions Patient-Focused Outcomes Patients Pattern Periodicity Reactive Oxygen Species Role Signal Transduction Site Source Staphylococcus aureus Stimulus Syndrome Therapeutic Intervention autoinflammatory chemical property cytochrome c cytokine fight against improved outcome influenzavirus macrophage mitochondrial dysfunction mitochondrial membrane novel oxidation pathogen physical property public health relevance recruit response targeted treatment 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炎性小体与保护性和病理性免疫反应有关。它的适当激活会触发对入侵病原体（包括流感病毒、金黄色葡萄球菌和白色念珠菌）的先天免疫反应，其过度反应是自身炎症综合征CAPS （crypyrin相关周期性综合征）的基础。Nlrp3炎症小体也可由代谢异常触发，导致痛风、II型糖尿病和动脉粥样硬化等常见衰弱性疾病的发展。我们已经确定了Nlrp3炎性体激活途径中的一个新步骤，揭示了以前未被认识到的与外源性凋亡途径激活的重叠。我们实验室的初步研究表明，与这些凋亡途径类似，Nlrp3炎性体激活诱导线粒体功能障碍，这可以通过线粒体内正常负电位的丧失来证明。在细胞凋亡过程中，线粒体膜电位的丧失与线粒体脂质心磷脂从线粒体内膜到外膜的易位有关。这种运动伴随着心磷脂的氧化及其结合伙伴细胞色素c向膜间空间的释放。线粒体外膜上的心磷脂招募并结合caspase-8， caspase-8反过来驱动线粒体外膜孔的产生，细胞色素c从心磷脂的束缚中解脱出来，通过这个孔进入细胞质，触发免疫沉默细胞死亡