Histone lactylation-induced GLI3 activation drives macrophage M1 polarization and exosomal SERPINE1 release in abdominal aortic aneurysm progression
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Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis
Published on: November 28, 2015
Kai Yuan1, Junjian Liu1, Guanghui Chen2
1Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
M1 macrophages promote the progression of abdominal aortic aneurysm (AAA). Lactate-mediated histone lactylation modification regulates macrophage M1 polarization. However, the role and molecular mechanisms of lactylation-mediated macrophage M1 polarization in AAA remain unclear. Histone lactylation in macrophages was investigated using clinical specimens and AAA animal models, with subsequent validation at the cellular level. Key genes undergoing lactylation modification were screened through RNA-seq and CUT&Tag joint analysis. Functional validation was conducted to demonstrate that the target genes mediate AAA progression by regulating macrophage M1 polarization and subsequent exosome-mediated endothelial dysfunction. We observed elevated serum lactate levels in AAA patients. H3K18 lactylation (H3K18la) and M1 macrophage marker CD86 were upregulated and co-localized in the aortic aneurysm of AAA mice. Lactate upregulated H3K18la levels and M1 polarization markers CD80, MCP-1, and iNOS, while downregulating M2 polarization marker CD206. Transcriptome sequencing identified 305 genes that were abnormally expressed in lactate-treated macrophages. A total of 839 differentially modified lactylation peaks were identified in lactate-treated macrophages, with 195 peaks enhanced and 644 peaks weakened. Notably, GLI3 was identified as a highly lactylated gene, and its knockdown significantly suppressed macrophage M1 polarization. Lactate induced macrophage M1 polarization by promoting GLI3 expression. Furthermore, lactate-polarized M1 macrophages induced endothelial dysfunction by secreting the exosomal protein SERPINE1. This study demonstrates that histone lactylation-mediated GLI3 activation drives macrophage M1 polarization and subsequent secretion of exosomal SERPINE1, inducing endothelial dysfunction in AAA progression. This study provides significant advances in our comprehensive understanding of AAA pathogenesis mediated by endothelial dysfunction.
Insights
Histone lactylation drives M1 macrophage polarization and abdominal aortic aneurysm (AAA) progression by activating GLI3 and promoting exosomal SERPINE1 secretion, leading to endothelial dysfunction.
Area of Science:
- Cardiovascular Biology
- Immunology
- Epigenetics
Background:
- Abdominal aortic aneurysm (AAA) progression is linked to M1 macrophages.
- Lactate-mediated histone lactylation influences M1 macrophage polarization, but its role in AAA is unclear.
Purpose of the Study:
- To investigate the role and molecular mechanisms of lactylation-mediated macrophage M1 polarization in AAA.
- To identify key lactylated genes involved in AAA pathogenesis.
Main Methods:
- Analysis of clinical AAA specimens and animal models.
- RNA-sequencing and CUT&Tag assays to identify lactylated genes.
- Cellular validation of gene function and macrophage polarization markers.
Main Results:
- Elevated serum lactate and H3K18 lactylation (H3K18la) in AAA patients and mice.
- Lactate upregulated M1 markers (CD80, MCP-1, iNOS) and H3K18la in macrophages.
- GLI3 identified as a key lactylated gene promoting M1 polarization.
- Lactate-polarized M1 macrophages secreted exosomal SERPINE1, causing endothelial dysfunction.
Conclusions:
- Histone lactylation-mediated GLI3 activation drives M1 macrophage polarization in AAA.
- Exosomal SERPINE1 secreted by M1 macrophages contributes to endothelial dysfunction and AAA progression.
- This study elucidates a novel epigenetic mechanism in AAA pathogenesis.
