Myeloid deficiency of Z-DNA binding protein 1 restricts septic cardiomyopathy via promoting macrophage polarisation towards the M2-subtype

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-04-27 DOI:10.1002/ctm2.70315

Yifan Shi, Lu He, Jie Ni, Yuyuan Zhou, Xiaohua Yu, Yao Du, Yang Li, Xi Tan, Yufang Li, Xiaoying Xu, Si Sun, Lina Kang, Biao Xu, Jibo Han, Lintao Wang

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引用次数: 0

Abstract

Background

Septic cardiomyopathy is a frequent complication in patients with sepsis and is associated with a high mortality rate. Given its clinical significance, understanding the precise underlying mechanism is of great value.

Methods and results

Our results unveiled that Z-DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)-treated mice. Single-cell mRNA sequencing (scRNA-seq) and single-nucleus mRNA sequencing (snRNA-seq) indicated that Zbp1 mRNA in endothelial cells, fibroblasts and macrophages appeared to be elevated by LPS, which is partially consistent with the results of immunofluorescence. Through echocardiography, we identified that global deletion of ZBP1 improves cardiac dysfunction and the survival rate of LPS-treated mice. Mechanistically, snRNA-seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2-subtype, which reduces inflammatory cell infiltration. Notably, myeloid-specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage-derived ZBP1 in septic myocardial dysfunction. Finally, we revealed that LPS increases the transcription and expression of ZBP1 through signal transducer and activator of transcription 1 (STAT1). Fludarabine, the inhibitor of STAT1, could also promote M2 macrophage polarisation and improve cardiac dysfunction of LPS-treated mice.

Conclusions

Our study provides evidence of a novel STAT1-ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage-derived ZBP1 as a therapeutic target for septic cardiomyopathy.

Key points

Macrophage-derivedZBP1 exacerbates LPS-induced myocardial dysfunction and inflammatory cellinfiltration.
Deletionof ZBP1 promotes macrophage polarisation from M1 to M2.
STAT1-ZBP1axis promotes septic cardiomyopathy.
ZBP1has emerged as a potential therapeutic target for inflammationand septic cardiomyopathy.

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髓系Z-DNA结合蛋白1缺乏通过促进巨噬细胞向m2亚型极化来限制脓毒性心肌病

背景：脓毒性心肌病是脓毒症患者的常见并发症，且死亡率高。鉴于其临床意义，了解其确切的潜在机制具有重要价值。方法与结果我们的研究结果揭示了Z-DNA结合蛋白1 （ZBP1）在脂多糖（LPS）处理小鼠心肌组织中表达上调。单细胞mRNA测序（scRNA-seq）和单核mRNA测序（snRNA-seq）结果显示，LPS作用下内皮细胞、成纤维细胞和巨噬细胞中Zbp1 mRNA表达明显升高，这与免疫荧光检测结果部分一致。通过超声心动图，我们发现ZBP1的整体缺失改善了lps治疗小鼠的心功能障碍和存活率。机制上，snRNA-seq显示ZBP1主要在巨噬细胞中表达，ZBP1的缺失促进巨噬细胞向m2亚型极化，从而减少炎症细胞浸润。值得注意的是，骨髓特异性的ZBP1缺失也促进M2巨噬细胞极化并改善心功能障碍，验证了巨噬细胞来源的ZBP1在脓毒性心肌功能障碍中的作用。最后，我们发现LPS通过信号换能器和转录激活器1 （STAT1）增加ZBP1的转录和表达。STAT1抑制剂氟达拉滨也能促进M2巨噬细胞极化，改善lps处理小鼠心功能障碍。我们的研究提供了新的STAT1-ZBP1轴在巨噬细胞促进脓毒性心肌病的证据，并强调了巨噬细胞来源的ZBP1作为脓毒性心肌病治疗靶点的潜力。巨噬细胞衍生的zbp1加重lps诱导的心肌功能障碍和炎症细胞浸润。ZBP1的缺失促进巨噬细胞从M1向M2极化。STAT1-ZBP1axis促进脓毒性心肌病。zbp1已成为炎症和脓毒性心肌病的潜在治疗靶点。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.