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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Epithelial Atg5 Deficiency Intensifies Caspase-11 Activation, Fueling Extracellular mtDNA Release to Activate
Junyi Wang1,2,3, Lei Zhang1,2,3, Yingying Liu3,4
1Laboratory of Allergy and Precision Medicine, Department of Respiratory Medicine, Chengdu Institute of Respiratory Health Affiliated Hospital of Southwest Jiaotong University, the Third People's Hospital of Chengdu Chengdu China.
Abstract:
Pseudomonas aeruginosa (P. aeruginosa) infections pose a significant threat to public health, underscoring the need for deeper insights into host cellular defenses. This study explores the critical role of autophagy-related protein 5 (ATG5) in lung epithelial cells during P. aeruginosa infection. Single-cell RNA transcriptomics revealed a pronounced enrichment of autophagy pathways in type II alveolar epithelial cells (AEC2). Using a conditional Atg5 knockout murine model, we demonstrated that ATG5 deficiency in AEC2 compromises survival, hampers bacterial clearance, and increases pathogen dissemination. Additionally, the loss of ATG5 exacerbated inflammatory responses, notably through the activation of the AKT/PI3K/NF-κB axis and pyroptosis, which culminated in severe lung injury and epithelial barrier disruption. Mechanistically, the absence of ATG5 disrupted mitophagy, leading to intensified mitochondrial damage. This exacerbated condition coupled with the activation of gasdermin D (GSDMD) by the noncanonical caspase-11, enhancing the release of mitochondrial DNA (mtDNA), which in turn activated cGAS-STING-NLRP3 signaling in macrophages. These findings highlight the essential role of ATG5 in modulating immune responses and suggest potential therapeutic targets for managing P. aeruginosa-induced pulmonary infections.
Insights
Autophagy protein 5 (ATG5) is crucial for lung epithelial cells to fight Pseudomonas aeruginosa infections. Its absence worsens inflammation, bacterial spread, and lung injury, highlighting ATG5 as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Pseudomonas aeruginosa infections are a major public health concern.
- Understanding host cellular defenses is critical for managing these infections.
- Autophagy plays a role in cellular defense mechanisms.
Purpose of the Study:
- To investigate the role of autophagy-related protein 5 (ATG5) in lung epithelial cells during P. aeruginosa infection.
- To elucidate the mechanisms by which ATG5 influences host defense and lung injury.
Main Methods:
- Single-cell RNA transcriptomics to identify enriched pathways in alveolar epithelial cells.
- Utilized a conditional Atg5 knockout murine model.
- Analyzed inflammatory responses, bacterial clearance, and lung pathology.
Main Results:
- Autophagy pathways were enriched in type II alveolar epithelial cells (AEC2).
- ATG5 deficiency in AEC2 impaired bacterial clearance, increased dissemination, and reduced survival.
- Loss of ATG5 exacerbated inflammation via AKT/PI3K/NF-κB and pyroptosis, leading to lung injury.
- ATG5 absence disrupted mitophagy, increased mitochondrial damage, and promoted mtDNA release, activating cGAS-STING-NLRP3 signaling.
Conclusions:
- ATG5 is essential for host defense against P. aeruginosa in lung epithelial cells.
- ATG5 regulates mitophagy and inflammatory signaling pathways, including pyroptosis.
- Targeting ATG5 may offer a therapeutic strategy for P. aeruginosa-induced pulmonary infections.
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