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Mast Cell-Derived CXCL4: A Key Mediator of Ferroptosis and Cardiac Damage in Septic Cardiomyopathy
Jing Wei1,2, Zhi-Ying Jiang1, Ling-Feng Ye1
1Department of Laboratory Medicine, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Insights
Mast cell-derived CXCL4 triggers macrophage ferroptosis and impairs phagocytosis, worsening septic cardiomyopathy. Targeting CXCL4 or the STAT3/P53 pathway offers potential SCM therapies.
Area of Science:
- Cardiology
- Immunology
- Cell Biology
Background:
- Septic cardiomyopathy (SCM) is a severe sepsis complication with high mortality and unclear mechanisms.
- CXCL4, a pro-inflammatory factor, and ferroptosis are implicated in SCM, but their interaction is unknown.
Purpose of the Study:
- To elucidate the crosstalk between CXCL4, ferroptosis, and SCM.
- To investigate the role of mast cell-derived CXCL4 in SCM pathogenesis.
- To identify potential therapeutic targets for SCM.
Main Methods:
- Established SCM models in mice using LPS injection and treated with inhibitors targeting mast cells, ferroptosis, STAT3, or P53.
- Performed in vivo and in vitro experiments including histopathology, survival analysis, ELISA, Western blot, immunofluorescence, and cell assays.
- Assessed myocardial markers, oxidative stress, and macrophage function.
Main Results:
- Elevated CXCL4 levels correlated with mast cell activation and SCM severity in mice.
- Inhibiting mast cells or targeting STAT3/P53 signaling reduced ferroptosis, improved macrophage function, and mitigated cardiac injury.
- CXCL4 induced macrophage ferroptosis and impaired phagocytosis via the STAT3/P53 pathway.
Conclusions:
- Mast cell-derived CXCL4 drives SCM by inducing macrophage ferroptosis and impairing phagocytosis through the STAT3/P53 pathway.
- Targeting mast cell activation, CXCL4, or the STAT3/P53-ferroptosis axis presents promising therapeutic strategies for SCM.
Background:
Septic cardiomyopathy (SCM) is a common and life-threatening complication of severe sepsis, with high mortality due to unclear underlying mechanisms. CXCL4, a key pro-inflammatory factor, is implicated in various heart diseases, while ferroptosis (iron and lipid hydrogen peroxide-dependent regulated cell death) plays a crucial role in SCM progression. However, the specific crosstalk between CXCL4, ferroptosis, and SCM remains unelucidated.
Methods:
BALB/c mice were randomly divided into six groups (Control, LPS, LPS + Sodium Cromoglycate (CS), LPS + Ferrostatin-1 (Fer-1), LPS + Pifithrin-α (PFT-α), LPS + Niclosamide) to establish the SCM model via intraperitoneal LPS injection. In vivo experiments included histopathological examination (H&E, toluidine blue staining), survival analysis, ELISA, Western blot, immunofluorescence, immunohistochemistry, TUNEL staining, and detection of myocardial markers (CK-MB, AST, LDH) and oxidative stress indicators (SOD, MDA, iron content). In vitro, RAW264.7 macrophages were treated with CXCL4 alone or combined with inhibitors (Fer-1, PFT-α, Niclosamide), followed by CCK-8 assay, ROS detection, qRT-PCR, Western blot, and phagocytosis microbead assay.
Results:
In vivo, SCM mice exhibited significantly elevated CXCL4 levels in serum and heart tissue, accompanied by mast cell activation and degranulation. Inhibiting mast cell activation (with CS) reduced CXCL4 production, alleviated cardiac inflammation and ferroptosis (increased SLC7A11/GPX4 expression, decreased 4-HNE), and improved survival. TUNEL staining revealed predominant macrophage death in SCM hearts. In vitro, CXCL4 induced macrophage ferroptosis (downregulated SLC7A11/GPX4) and impaired phagocytic function (reduced CD36/MERTK expression), which was reversed by Fer-1. Mechanistically, CXCL4 activated STAT3 phosphorylation, regulating downstream P53; inhibiting STAT3 (Niclosamide) or P53 (PFT-α) alleviated macrophage ferroptosis, restored phagocytosis, and mitigated cardiac injury in SCM mice.
Conclusion:
Mast cell-derived CXCL4 induces macrophage ferroptosis via the STAT3/P53 signaling pathway, impairs macrophage phagocytic function, and exacerbates myocardial injury in SCM. Targeting mast cell activation, CXCL4 release, or the STAT3/P53-ferroptosis axis may serve as promising therapeutic strategies for SCM.
Clinical Trial Number:
Not applicable.
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