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Autophagic regulation of inflammasome-mediated hyperactive state in living macrophages

活体巨噬细胞中炎症小体介导的过度活跃状态的自噬调节

基本信息

批准号：
10288904
负责人：
Venkat Giri Magupalli
金额：
$ 23.36万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288904
关键词：
Acute Address Antibodies Autophagocytosis Autophagosome Binding Biological Biological Assay CASP1 gene COVID-19 Caspase Cell Death Cell membrane Cells Chemosensitization Chronic Disease Clinical Colitis Complex Coupled Cystic Fibrosis Transmembrane Conductance Regulator Dynein ATPase Family Dasypodidae Genes HDAC6 gene Hematopoietic Host Defense Hyperactivity Immune response Infection Inflammasome Inflammation Inflammatory Injections Interleukin-1 Interleukin-1 beta Interleukin-18 Interleukins Lead Leucine-Rich Repeat Ligands Light Link Lipids Lipopolysaccharides Lysosomes Lytic Macrophage activation syndrome Mediating Membrane Membrane Lipids Microtubule-Organizing Center Microtubules Mitochondria Mus Nigericin Nucleotides Outcome Pathway interactions Peptide Hydrolases Pericentriolar Regions Phenotype Phosphorylcholine Process Proteins Publishing Regulation Reporting Role Science Signal Transduction Sodium Dextran Sulfate Sterility Stimulus System Time Toll-like receptors Yang Yin cellular imaging cytokine cytokine release syndrome human disease live cell imaging macrophage misfolded protein oxidation pathogen presenilin-1 protein aggregation recruit repaired response retrograde transport tissue injury

项目摘要

Abstract Nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing proteins (NLRs) assemble into functional supramolecular organizing centers called the inflammasomes, which serve as an interface of host defense against pathogens or other types of danger. Canonical inflammasomes activate caspase-1, an inflammatory protease that upon activation, triggers two important biological responses: 1) processing of cytokine interleukin-1b (IL-1b), and 2) formation of plasma membrane gasdermin D pores to potentiate inflammatory cell death (pyroptosis). Cytokine secretion and pyroptosis are coupled under a steady-state condition, as the GSDMD pores on the plasma membrane, which permeates IL-1b, can also compromise the cell membrane integrity leading to the lytic cell death. Interestingly, in a hyperactive state following inflammasome activation, cells show sustained cytokine secretion but retain viability, even though this process is dependent on GSDMD pores formed on the plasma membrane. The underlying mechanisms which recalibrate GSDMD to only sustain the release of the interleukin, but not pyroptosis, are poorly understood. Autophagy is regarded as an important regulator of inflammation. In our recent studies, we found that inflammasomes are regulated by an aggresome-like mechanism that promotes inflammasome assembly (Yang) but also induces autophagy to dampen caspase-1 processing and IL-b secretion (Yin) (Magupalli et al., Science, 2020). Our studies are consistent with previous reports showing that mice lacking the key autophagic gene, Atg16L1, in hematopoietic cells, were highly susceptible to dextran sulphate sodium-induced acute colitis, with the secretion of a high amount of IL-1b and IL-18 cytokines. In addition, these inflammatory phenotypes were alleviated by injection of anti-IL-1b and IL-18 antibodies in mice. Collectively, our and other published results demonstrate that autophagy directly regulates the extent to which inflammasomes activate downstream signals. However, it is unclear if autophagy can regulate the switch between a hyperactive state and a pyroptotic state of macrophages. In this application, we will investigate the potential link between autophagy and macrophage hyperactivation using inflammasome assays and cellular imaging.

摘要