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Alternative pathways of gasdermin function and IL-1beta secretion in granulocytic leukocytes

粒细胞白细胞中 Gasdermin 功能和 IL-1β 分泌的替代途径

基本信息

批准号：
10223157
负责人：
GEORGE R DUBYAK
金额：
$ 41万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2020-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10223157
关键词：
Allergic Allergic Disease Apoptosis Apoptotic Autoimmune Autophagocytosis Autophagosome Biology CASP1 gene Caspase Cell Death Cell membrane Cells Cessation of life Cleaved cell Cytoplasmic Granules Cytosol DNA Data Effector Cell Exocytosis Extravasation Family Feedback Functional disorder Homeostasis Human Immune Immune signaling Immunization Inflammasome Inflammatory Innate Immune Response Interleukin-1 beta Leukocyte Elastase Leukocytes Lytic Mediating Membrane Lipids Metalloproteases Molecular Chaperones Mononuclear Myelogenous Natural Immunity Nonlytic Nuclear Envelope Pathway interactions Physiological Play Process Production Property Protease Inhibitor Protein Family Proteins Regulation Reporting Role Secondary to Secretory Vesicles Serine Protease Serpins Shapes Signal Transduction Signaling Protein Source Stimulus Testing Tissues acute infection base cell type chronic inflammatory disease cytokine eosinophil extracellular granulocyte macrophage mast cell neutrophil novel public health relevance response senescence trafficking

项目摘要

Abstract This project aims to define novel signaling mechanisms for the regulation of innate immune responses by Gasdermins D and E (GSDMD/E) in granulocytic leukocytes that include neutrophils, mast cells, and eosinophils. Physiological roles for GSDMD in both pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages and other mononuclear myeloid leukocytes. This involves cleavage of GSDMD by caspase-1 to generate N-GSDMD fragments which oligomerize in the plasma membrane (PM) to form pores that mediate IL-1β efflux and pyroptosis. Notably, the granulocytic myeloid leukocytes are also important sources of IL-1β during multiple innate immune responses, but few studies have examined roles for GSDMD or other GSDM-family proteins in these cells. Our preliminary data shows that caspase-1-generated N-GSDMD in neutrophils does not localize to the PM to form pores or drive pyroptosis but is required for IL-1β secretion. This absence of PM pores reflects alternative subcellular trafficking whereby N-GSDMD associates with azurophilic secretory granules (AG) and LC3+ autophagosomes. Analyses using ATG7-deficient neutrophils indicate that IL-1β is secreted from neutrophils via an autophagy machinery-assisted mechanism. These findings reveal fundamental differences in GSDM biology, including high expression of GSDME, between granulocytes and macrophages that will shape granulocyte roles in innate immunity. We hypothesize that the abundant secretory granules which define neutrophils, mast cells and eosinophils underlie granulocyte-specific mechanisms for non-canonical production of bioactive IL-1β and for regulated cell death via alternative pathways of GSDM family processing and subcellular trafficking. In Aim 1, we will define signaling hierarchies based on activation of inflammatory caspases, granule-derived serine proteases, apoptotic caspases, GSDMD, and GSDME that facilitate alternative paths of bioactive IL-1β production by neutrophils, mast cells, and eosinophils. Studies will include analyses of GSDMD/E trafficking to secretory granules versus the plasma membrane and GSDMD's ability to act as a chaperone for autophagy protein-assisted secretion of proIL-1β that can be extracellularly cleaved by serine proteases. In Aim 2, we will define GSDMD/E signaling networks that regulate granulocyte death pathways which are induced by triggers of extracellular DNA trap release/ETosis, apoptosis, and progression to granulocyte senescence. The project will draw on the strengths of the other three projects to facilitate our functional studies. The results will define novel mechanisms for how GSDMD and GSDME mediate granulocyte-specific signaling responses which play physiological roles during acute infection but contribute to tissue dysfunction in humans with common autoimmune, allergic, or chronic inflammatory diseases.

摘要