circ-Katnal1 Enhances Inflammatory Pyroptosis in Sepsis-Induced Liver Injury through the miR-31-5p/GSDMD Axis
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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
Kai Kang1, Nana Li1, Yang Gao2
1Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province, China.
Background:
Sepsis is a systemic inflammatory response that can elicit organ dysfunction as well as circulatory diseases in serious cases. When inflammatory responses are especially dysregulated, severe complications can arise, including sepsis-induced liver injury. Various microRNAs along with circular (circ) RNAs are involved in inflammatory responses; nevertheless, their functions in regulating sepsis-induced liver injury remain unknown. The cecal ligation and puncture (CLP) procedure can induce liver injury as well as polymicrobial sepsis.
Methods:
In this study, CLP was used to induce liver injury as well as polymicrobial sepsis. Then, liver function, inflammatory cytokine expression, and hepatic histopathology were evaluated. High-throughput sequencing was employed to investigate the abnormal hepatic circRNA expression after CLP. Raw264.7 cells were utilized to simulation an in vitro sepsis inflammation model with LPS induce. The relative mRNA as well as protein levels of TNF-α, IL-1β, and IL-6 was explored by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. We explored functional connections among circRNAs, miR-31-5p, and gasdermin D (GSDMD) using dual-luciferase reporter assays. Western blot was employed to test GSDMD, caspase-1, and NLRP3 expression in mice and cell models.
Results:
Our results showed that CLP-induced sepsis promoted liver injury via increasing inflammatory pyroptosis. The abnormal expression of circ-Katnal1 played an important role in CLP-induced sepsis. Downregulating circ-Katnal1 suppressed LPS-induced inflammatory pyroptosis in Raw264.7 cells. Bioinformatics and luciferase reporter results confirmed that miR-31-5p and GSDMD were downstream targets of circ-Katnal1. Inhibiting miR-31-5p or upregulating GSDMD reversed the protective effects of silencing circ-Katnal1.
Conclusion:
Taken together, circ-Katnal1 enhanced inflammatory pyroptosis in sepsis-induced liver injury through the miR-31-5p/GSDMD axis.
Insights
Circular RNA circ-Katnal1 exacerbates sepsis-induced liver injury by promoting inflammatory pyroptosis via the miR-31-5p/GSDMD pathway. This finding offers new insights into sepsis pathogenesis and potential therapeutic targets for liver damage.
Area of Science:
- Molecular Biology
- Immunology
- Hepatology
Background:
- Sepsis is a life-threatening systemic inflammatory response that can lead to organ dysfunction, particularly sepsis-induced liver injury.
- The roles of microRNAs and circular RNAs in regulating sepsis-induced liver injury are not well understood.
- The cecal ligation and puncture (CLP) model is established to induce polymicrobial sepsis and associated liver injury.
Purpose of the Study:
- To investigate the function of circular RNAs in sepsis-induced liver injury.
- To elucidate the molecular mechanisms underlying the regulation of inflammatory pyroptosis in sepsis-induced liver injury.
- To identify specific circRNAs involved in the pathogenesis of sepsis-induced liver injury.
Main Methods:
- Cecal ligation and puncture (CLP) model in mice to induce sepsis and liver injury.
- High-throughput sequencing to identify differentially expressed circRNAs in liver tissue post-CLP.
- In vitro sepsis model using Raw264.7 cells stimulated with lipopolysaccharide (LPS).
- Quantitative PCR, ELISA, and Western blot to assess inflammatory markers and protein expression.
- Dual-luciferase reporter assays to confirm interactions between circRNAs, microRNAs, and target genes.
Main Results:
- CLP-induced sepsis significantly promoted liver injury by increasing inflammatory pyroptosis.
- Circ-Katnal1 was identified as a significantly dysregulated circRNA in CLP-induced liver injury.
- Downregulation of circ-Katnal1 suppressed LPS-induced inflammatory pyroptosis in vitro.
- Bioinformatics and luciferase assays confirmed that circ-Katnal1 targets miR-31-5p and gasdermin D (GSDMD).
- Inhibition of miR-31-5p or upregulation of GSDMD reversed the protective effects of circ-Katnal1 silencing.
Conclusions:
- Circ-Katnal1 plays a critical role in exacerbating sepsis-induced liver injury.
- The circ-Katnal1/miR-31-5p/GSDMD axis promotes inflammatory pyroptosis in sepsis-induced liver injury.
- Targeting circ-Katnal1 may represent a novel therapeutic strategy for sepsis-induced liver injury.
