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Role of IRF1 in NLRP3 inflammasome activation and inflammatory diseases

IRF1在NLRP3炎症小体激活和炎症疾病中的作用

基本信息

批准号：
9599233
负责人：
Zhenyu Zhong
金额：
$ 16.2万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-24 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9599233
关键词：
Ablation Accounting Adaptor Signaling Protein Affect Aging Alzheimer&apos s Disease Atherosclerosis Autoimmune Process Biology CASP1 gene Cells Chronic Degenerative Disorder Development Disease Event Family Gout Gouty Arthritis Health Hepatitis Homeostasis Human IRF1 gene Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-18 Knowledge Lead Lupus Macular degeneration Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolic dysfunction Mitochondria Mitochondrial DNA Molecular Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nucleic Acids Oxides Pathogenesis Pathogenicity Pathologic Pathway interactions Pattern Pattern recognition receptor Periodicity Phosphotransferases Play Poison Process Role Sepsis Signal Pathway Signal Transduction Stimulus Syndrome Testing Tissues autoinflammatory base body sense cytokine fly immunopathology in vivo macrophage novel pathogen pathogenic microbe prevent protein complex receptor recruit repaired response restoration sensor tissue regeneration tissue repair virtual

项目摘要

Abstract Perturbation of homeostasis, as a result of pathogen invasion or self imbalance, can result in tissue damage and chronic inflammation. In addition to its well-established role in clearance of pathogens or cell corpses, inflammation also promotes tissue repair and regeneration. Conserved from flies to humans, a transient and properly terminated inflammatory response is crucial for restoration of tissue homeostasis after damage and its absence enhances tissue damage, leading to severe immunopathology. A key player in normal and pathological inflammation is the NLRP3 inflammasome, a major sensor of tissue damage, toxic substances and certain pathogens. Aberrant NLRP3 inflammasome activation has been shown to promote the development of gouty arthritis, lupus, atherosclerosis, Alzheimer's disease, macular degeneration and cancer. It is therefore of utmost importance to study the molecular mechanism involved in NLRP3 inflammasome activation during health and disease. NLRP3 inflammasome activation occurs via two distinct steps: “priming” and “activation”. Although different events involved in the “activation” step have been identified, the signaling steps through which NLRP3 inflammasome is activated remains unclear. Even less is understood about “priming”, which entails synthesis of the caspase-1 substrate pro-IL-1β as well as elevated NLRP3 expression. Recently, I identified interferon regulatory factor 1 (IRF1) as a novel player that is required for NLRP3 inflammasome activation. Of note, LPS- mediated priming results in strong IRF1 induction whereas IRF1 ablation prevents NLRP3 activation without affecting expression of pro-IL-1β or components of the inflammasome. This proposal aims at delineating the entire signaling pathway through which IRF1 controls NLRP3 inflammasome activation, and determining the role of this pathway in the pathogenesis of NLRP3-associated inflammatory disorders. Completion of this study will not only further our knowledge on inflammasome biology, but also provide a new way to interfere with aberrant NLRP3 inflammasome activation in a number of inflammatory diseases.

摘要