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<p>Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality globally, often leading to heart failure due to excessive inflammation and fibrosis. Thymic stromal lymphopoietin (TSLP), a cytokine primarily involved in immune regulation, has recently been identified as a key player in cardiovascular health. However, its role in modulating inflammation and fibrosis after AMI is not fully understood. This study investigates how TSLP mediates anti-inflammatory effects and reduces fibrosis, ultimately improving heart function in a mouse model of AMI. We established a TSLP knockout mouse strain and performed left anterior descending (LAD) coronary artery ligation to create an AMI model. This was used to investigate the role of TSLP in eosinophil (EOS) recruitment and fibrosis alleviation. Additionally, EOS depletion, JAK-STAT pathway inhibition, and ferroptosis were employed to analyze potential mediating factors. The extent of cardiac tissue fibrosis was evaluated using histological staining. Inflammatory cytokine levels and EOS were assessed through ELISA and flow cytometry. Western blotting was conducted to detect proteins related to ferroptosis and the JAK-STAT pathway. TSLP deficiency significantly exacerbated myocardial remodeling in AMI mice, while TSLP treatment markedly reduced cardiac fibrosis following AMI, with a notable decrease in collagen deposition within the heart tissue. In Transwell assays, TSLP effectively recruited EOSs, and in vivo experiments demonstrated that TSLP promoted the resolution of acute-phase inflammation (within one week), a process that could be blocked by EOS depletion. TSLP promotes the resolution of post-infarction inflammation and inhibits fibrosis by recruiting EOSs to the heart. This highlights the potential of targeting the TSLP-EOS axis as a therapeutic strategy to improve cardiac function and reduce post-AMI complications.</p> Graphical abstract <p>This schematic illustrates the role of TSLP in regulating eosinophil (EOS) recruitment and protecting cardiomyocytes following acute myocardial infarction (AMI). Under pathological conditions, reduced TSLP expression leads to overactivation of the JAK1–STAT5 pathway, repression of <i>SLC7A11</i> transcription, increased ferroptosis, and mitochondrial damage, accompanied by impaired EOS recruitment and excessive fibrosis. In contrast, TSLP supplementation inhibits the JAK1 pathway, promotes EOS recruitment, downregulates pro-inflammatory cytokine expression, restores mitochondrial structural integrity, and suppresses ferroptosis by upregulating SLC7A11 and glutathione (GSH) synthesis, thereby facilitating optimal fibrotic repair.</p>

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TSLP mitigates post-infarction myocardial remodeling by promoting eosinophil recruitment and inhibiting JAK1–STAT5-mediated ferroptosis

  • 期刊论文

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  • 发表日期：

    2025年7月5日

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  • Yunzhe Wang,
  • Chenxi Cao,
  • Tinglan Fu,
  • Fengyi Yu,
  • Jinyue Qi,
  • Gangqiong Liu,
  • Jinying Zhang

摘要

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality globally, often leading to heart failure due to excessive inflammation and fibrosis. Thymic stromal lymphopoietin (TSLP), a cytokine primarily involved in immune regulation, has recently been identified as a key player in cardiovascular health. However, its role in modulating inflammation and fibrosis after AMI is not fully understood. This study investigates how TSLP mediates anti-inflammatory effects and reduces fibrosis, ultimately improving heart function in a mouse model of AMI. We established a TSLP knockout mouse strain and performed left anterior descending (LAD) coronary artery ligation to create an AMI model. This was used to investigate the role of TSLP in eosinophil (EOS) recruitment and fibrosis alleviation. Additionally, EOS depletion, JAK-STAT pathway inhibition, and ferroptosis were employed to analyze potential mediating factors. The extent of cardiac tissue fibrosis was evaluated using histological staining. Inflammatory cytokine levels and EOS were assessed through ELISA and flow cytometry. Western blotting was conducted to detect proteins related to ferroptosis and the JAK-STAT pathway. TSLP deficiency significantly exacerbated myocardial remodeling in AMI mice, while TSLP treatment markedly reduced cardiac fibrosis following AMI, with a notable decrease in collagen deposition within the heart tissue. In Transwell assays, TSLP effectively recruited EOSs, and in vivo experiments demonstrated that TSLP promoted the resolution of acute-phase inflammation (within one week), a process that could be blocked by EOS depletion. TSLP promotes the resolution of post-infarction inflammation and inhibits fibrosis by recruiting EOSs to the heart. This highlights the potential of targeting the TSLP-EOS axis as a therapeutic strategy to improve cardiac function and reduce post-AMI complications.

Graphical abstract

This schematic illustrates the role of TSLP in regulating eosinophil (EOS) recruitment and protecting cardiomyocytes following acute myocardial infarction (AMI). Under pathological conditions, reduced TSLP expression leads to overactivation of the JAK1–STAT5 pathway, repression of SLC7A11 transcription, increased ferroptosis, and mitochondrial damage, accompanied by impaired EOS recruitment and excessive fibrosis. In contrast, TSLP supplementation inhibits the JAK1 pathway, promotes EOS recruitment, downregulates pro-inflammatory cytokine expression, restores mitochondrial structural integrity, and suppresses ferroptosis by upregulating SLC7A11 and glutathione (GSH) synthesis, thereby facilitating optimal fibrotic repair.