Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Front Immunol. 2023 May 3;14:1087978. doi: 10.3389/fimmu.2023.1087978. eCollection 2023.
At present, research on immunogenic cell death (ICD) is mainly associated with cancer therapy. Little is known about the role of ICD in cardiovascular disease, especially in ascending thoracic aortic aneurysms (ATAA).
ATAA single-cell RNA (scRNA) sequencing data were analyzed to identify the involved cell types and determine their transcriptomic characteristics. The chi-square test, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Gene Set Enrichment Analysis (GSEA), and CellChat for cell-to-cell communication analysis from the Gene Expression Omnibus (GEO) database were used.
A total of 10 cell types were identified, namely, monocytes, macrophages, CD4 T/NK (CD4+ T cells and natural killer T cells), mast cells, B/Plasma B cells, fibroblasts, endothelial cells, cytotoxic T cells (CD8+ T cells, CTLs), vascular smooth muscle cells (vSMCs), and mature dendritic cells (mDCs). A large number of inflammation-related pathways were present in the GSEA results. A large number of ICD-related pathways were found in the KEGG enrichment analysis of differentially expressed genes in endothelial cells. The number of mDCs and CTLs in the ATAA group was significantly different from that in the control group. A total of 44 pathway networks were obtained, of which 9 were associated with ICD in endothelial cells (CCL, CXCL, ANNEXIN, CD40, IL1, IL6, TNF, IFN-II, GALECTIN). The most important ligand-receptor pair by which endothelial cells act on CD4 T/NK cells, CTLs and mDCs is CXCL12-CXCR4. The most important ligand-receptor pair by which endothelial cells act on monocytes and macrophages is ANXA1-FPR1. The most important ligand-receptor pair by which CD4 T/NK cells and CTLs act on endothelial cells is CCL5-ACKR1. The most important ligand-receptor pair that myeloid cells (macrophages, monocytes and mDCs) act on endothelial cells is CXCL8-ACKR1. Moreover, vSMCs and fibroblasts mainly promote inflammatory responses through the MIF signaling pathway.
ICD is present in ATAA and plays an important role in the development of ATAA. The target cells of ICD may be mainly endothelial cells, in which the aortic endothelial cell ACKR1 receptor can not only promote T-cell infiltration through the CCL5 ligand but also promote myeloid cell infiltration through the CXCL8 ligand. ACKR1 and CXCL12 may become target genes for ATAA drug therapy in the future.
目前，免疫原性细胞死亡（ICD）的研究主要与癌症治疗相关。关于 ICD 在心血管疾病中的作用，尤其是在升主动脉瘤（ATAA）中的作用，知之甚少。
对 ATAA 单细胞 RNA（scRNA）测序数据进行分析，以鉴定涉及的细胞类型并确定其转录组特征。使用卡方检验、基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析、基因集富集分析（GSEA）以及从基因表达综合数据库（GEO）进行细胞间通讯分析的 CellChat。
共鉴定出 10 种细胞类型，分别为单核细胞、巨噬细胞、CD4 T/NK（CD4+ T 细胞和自然杀伤 T 细胞）、肥大细胞、B/浆细胞 B 细胞、成纤维细胞、内皮细胞、细胞毒性 T 细胞（CD8+ T 细胞、CTL）、血管平滑肌细胞（vSMCs）和成熟树突状细胞（mDCs）。在 GSEA 结果中存在大量与炎症相关的途径。在内皮细胞差异表达基因的 KEGG 富集分析中发现了大量与 ICD 相关的途径。ATAA 组的 mDCs 和 CTLs 数量与对照组有显著差异。共获得 44 条通路网络，其中 9 条与内皮细胞中的 ICD 相关（CCL、CXCL、ANNEXIN、CD40、IL1、IL6、TNF、IFN-II、GALECTIN）。内皮细胞作用于 CD4 T/NK 细胞、CTL 和 mDCs 的最重要配体-受体对是 CXCL12-CXCR4。内皮细胞作用于单核细胞和巨噬细胞的最重要配体-受体对是 ANXA1-FPR1。CD4 T/NK 细胞和 CTLs 作用于内皮细胞的最重要配体-受体对是 CCL5-ACKR1。髓样细胞（巨噬细胞、单核细胞和 mDCs）作用于内皮细胞的最重要配体-受体对是 CXCL8-ACKR1。此外，vSMCs 和成纤维细胞主要通过 MIF 信号通路促进炎症反应。
ICD 存在于 ATAA 中，在 ATAA 的发生发展中起重要作用。ICD 的靶细胞可能主要是内皮细胞，其中主动脉内皮细胞 ACKR1 受体不仅可以通过 CCL5 配体促进 T 细胞浸润，还可以通过 CXCL8 配体促进髓样细胞浸润。ACKR1 和 CXCL12 可能成为未来 ATAA 药物治疗的靶基因。
