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

• 批准号: 10755554
• 负责人: Venkat Giri Magupalli
• 金额: $ 16.52万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10755554
• 关键词: Autophagic; regulation; inflammasome; mediated; hyperactive

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