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GATA6 regulates macrophage polarization via the CSF1 signaling pathway in acute myocardial infarction
Tianhe Xia1, Yewen Xu1, Rongzhou Wu1
1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Insights
Transcription factor GATA binding protein 6 (GATA6) promotes anti-inflammatory macrophage polarization after myocardial infarction (MI). GATA6 loss exacerbates cardiac injury by impairing this crucial macrophage response.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Macrophage inflammation is central to myocardial infarction (MI) and cardiac remodeling.
- Transcriptional regulation of macrophage polarization in the infarcted heart is not fully understood.
- The role of transcription factor GATA binding protein 6 (GATA6) in MI is undefined.
Purpose of the Study:
- To investigate the role of GATA6 in regulating macrophage polarization post-myocardial infarction.
- To elucidate the molecular mechanisms by which GATA6 influences macrophage responses in the infarcted heart.
Main Methods:
- Established a murine myocardial infarction (MI) model using coronary artery ligation.
- Utilized myeloid-specific Gata6 deletion (LysM-Cre) to assess in vivo GATA6 function.
- Evaluated macrophage polarization and inflammatory markers via flow cytometry, qPCR, ELISA, immunofluorescence, and Western blotting; employed in vitro hypoxia models and rescue experiments with recombinant CSF1.
Main Results:
- GATA6 expression increased in macrophages at the infarct border zone post-MI.
- GATA6 deficiency impaired hypoxia-induced CSF1 expression, reduced ERK phosphorylation, and decreased anti-inflammatory macrophage (CD206+) polarization and IL-10 secretion.
- Myeloid-specific Gata6 deletion in vivo worsened cardiac function, increased infarct size, and elevated inflammatory cytokine levels post-MI.
Conclusions:
- GATA6 promotes anti-inflammatory-like macrophage polarization via the CSF1/ERK signaling pathway.
- GATA6 plays a protective role in limiting myocardial injury following myocardial infarction.
Background:
Macrophage-mediated inflammation plays a crucial role in myocardial infarction (MI) and subsequent cardiac remodeling. However, the transcriptional mechanisms regulating macrophage polarization in the infarcted heart remain incompletely understood. GATA binding protein 6 (GATA6) is a transcription factor involved in macrophage identity, but its role in myocardial infarction has not been fully defined.
Methods:
A murine MI model was established by permanent ligation of the left anterior descending coronary artery. LysM-Cre-mediated myeloid-specific Gata6 deletion was used to evaluate the in vivo function of GATA6. Macrophage responses were assessed using immunofluorescence staining, flow cytometry, Western blotting, quantitative PCR, and ELISA. In vitro experiments were performed in RAW264.7 macrophages exposed to hypoxia. Recombinant CSF1 was used in rescue experiments.
Results:
GATA6 expression was markedly increased in F4/80-positive macrophages within the infarct border zone after MI. GATA6 deficiency reduced hypoxia-induced Csf1 expression and attenuated ERK phosphorylation. Loss of GATA6 decreased the proportion of CD206-positive macrophages and reduced IL-10 secretion, while additional polarization-associated markers further supported impaired anti-inflammatory-like polarization. Recombinant CSF1 restored ERK activation and macrophage polarization in GATA6-deficient cells. In vivo, myeloid-specific Gata6 deletion increased infarct size, impaired cardiac function, reduced CD206-positive F4/80-positive macrophages, and increased inflammatory cytokine responses after MI.
Conclusions:
GATA6-associated CSF1/ERK signaling promotes anti-inflammatory-like macrophage polarization and limits myocardial injury after myocardial infarction.