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Updated: May 17, 2025
A Controlled Mouse Model for Neonatal Polymicrobial Sepsis
Published on: January 27, 2019
MAPK14 drives Ferroptosis and immune dysfunction in pediatric Sepsis-induced acute lung injury
Ning Zhang1, Yuanyuan Fan2, Juan Chen3
1Department of Surgery Intensive Care Unit (SICU), Children's Hospital of Soochow University, Suzhou, Jiangsu 215008, China.
Objective:
Sepsis-induced acute lung injury (ALI) is driven by inflammation, oxidative stress, and immune suppression. MAPK14 (p38α) plays a role in ferroptosis and immune regulation, but its specific function in pediatric sepsis remains unclear. Therefore, our study aimed to explore the role and underlying mechanism of MAPK14 in pediatric sepsis.
Methods:
Bioinformatics analysis of GSE26440 and FerrDb identified ferroptosis-related genes in pediatric sepsis. STRING database was used to predict the proteins associated with MAPK14. MAPK14 expression in whole blood samples, LPS-treated MLE-12 cells, and a CLP mouse model was detected by qRT-PCR and western blot. Ferroptosis was assessed by measuring MDA, GSH, and Fe2+ levels, while ROS accumulation was analyzed using DCFH-DA staining and DHE staining. A cycloheximide (CHX) assay was performed to assess TTP53 protein stability. MPO immunohistochemistry and PD-L1 immunofluorescence assessed neutrophil infiltration, and flow cytometry evaluated neutrophil apoptosis.
Results:
Bioinformatics analysis of GSE26440 and FerrDb identified MAPK14 as a ferroptosis-related gene in pediatric sepsis. MAPK14 expression was upregulated in sepsis patient samples, LPS-treated MLE-12 cells and CLP mouse lung tissues. Overexpression of MAPK14 led to increased MDA and Fe2+ levels, reduced GSH, and elevated ROS fluorescence intensity, confirming its role in promoting ferroptosis. Mechanistically, MAPK14 upregulated TTP53, which in turn suppressed SLC7A11 and GPX4, further driving ferroptosis. MAPK14 overexpression stabilized TTP53 and enhanced its activity. Additionally, MAPK14 enhanced MPO and PD-L1 expression to promote neutrophil infiltration and immune suppression. Additionally, MAPK14 overexpression inhibited neutrophil apoptosis, promoted neutrophil infiltration and enhanced immune suppression.
Conclusion:
MAPK14 drives ferroptosis via the TTP53/SLC7A11/GPX4 pathway and exacerbates immune suppression by promoting neutrophil infiltration.
Insights
Mitogen-activated protein kinase 14 (MAPK14) promotes ferroptosis and immune suppression in pediatric sepsis by upregulating TTP53, exacerbating acute lung injury.
Area of Science:
- Cellular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis-induced acute lung injury (ALI) involves inflammation, oxidative stress, and immune suppression.
- Mitogen-activated protein kinase 14 (MAPK14), also known as p38α, is implicated in ferroptosis and immune regulation, but its role in pediatric sepsis is not well understood.
Purpose of the Study:
- To investigate the role and underlying mechanisms of MAPK14 in pediatric sepsis-induced ALI.
- To elucidate the specific pathways through which MAPK14 influences ferroptosis and immune responses in this context.
Main Methods:
- Bioinformatic analysis of gene expression datasets (GSE26440) and ferroptosis databases (FerrDb) to identify relevant genes.
- Quantitative real-time PCR (qRT-PCR) and Western blot to measure MAPK14 expression in patient samples, cell lines, and a mouse model.
- Assessment of ferroptosis markers (MDA, GSH, Fe2+, ROS) and neutrophil activity (MPO, PD-L1, apoptosis).
Main Results:
- MAPK14 was identified as a ferroptosis-related gene and was upregulated in pediatric sepsis.
- MAPK14 overexpression promoted ferroptosis by upregulating TTP53, which suppressed SLC7A11 and GPX4.
- MAPK14 enhanced neutrophil infiltration and immune suppression by increasing MPO and PD-L1 expression, while inhibiting neutrophil apoptosis.
Conclusions:
- MAPK14 plays a critical role in driving ferroptosis through the TTP53/SLC7A11/GPX4 pathway in pediatric sepsis.
- MAPK14 exacerbates immune suppression by promoting neutrophil infiltration, contributing to the pathogenesis of sepsis-induced ALI.
