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| Status |
Public on Oct 10, 2024 |
| Title |
Decoding the Multiple Functions of ZBP1 in the Mechanism of Sepsis-Induced Acute Lung Injury |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Sepsis-induced acute lung injury (ALI), characterized by severe hypoxemia and pulmonary leakage, remains a leading cause of mortality in intensive care units. The exacerbation of ALI during sepsis is largely attributed to uncontrolled inflammatory responses and endothelial dysfunction. Emerging evidences suggest an important role of Z-DNA binding protein 1 (ZBP1) as a sensor in innate immune to drive inflammatory signaling and cell death during infections. However, the role of ZBP1 in sepsis-induced ALI has yet to be defined. We utilized ZBP1 knockout mice and combined single-cell RNA sequencing with experimental validation to investigate ZBP1's roles in the regulation of macrophages and lung endothelial cells during sepsis. We demonstrate that in sepsis, ZBP1 deficiency in macrophages reduces mitochondrial damage and inhibits glycolysis, thereby altering the metabolic status of macrophages. Consequently, this metabolic shift leads to a reduction in the differentiation of macrophages into pro-inflammatory states and decreases macrophage pyroptosis triggered by activation of the NLRP3 inflammasome. These changes significantly weaken the inflammatory signaling pathways between macrophages and endothelial cells, and alleviate endothelial dysfunction and cellular damage. These findings reveal important roles for ZBP1 in mediating multiple pathological processes involved in sepsis-induced ALI by modulating the functional states of macrophages and endothelial cells, thereby highlighting its potential as a promising therapeutic target.
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| Overall design |
These cells were isolated from the lungs of WT and Zbp1-/- mice at 24 hours post-CLP and sham procedures.
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| Contributor(s) |
Gong T, Fu Y, Wang Q, Loughran P, Li Y, Billiar T, Wen Z, Liu Y, Fan J |
| Citation missing |
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| |
| Submission date |
Oct 04, 2024 |
| Last update date |
Oct 11, 2024 |
| Contact name |
Jie Fan |
| E-mail(s) |
jif7@pitt.edu
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| Organization name |
University of Pittsburgh School of Medicine
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| Department |
Department of Surgery
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| Lab |
Dr. Fan's Lab
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| Street address |
200 Lothrop Street
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| City |
Pittsburgh |
| ZIP/Postal code |
15213 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (14)
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| Relations |
| BioProject |
PRJNA1168866 |
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