Caspase-12 exhibits non-redundant functions in response to endoplasmic reticulum stress to promote GSDMD-mediated NETosis, leading to thoracic aortic dissection

IF 6.4 2区医学 Q1 MEDICAL LABORATORY TECHNOLOGY

Translational Research Pub Date : 2025-02-25 DOI:10.1016/j.trsl.2025.02.005

Hanchuan Chen , Kun Yang , Shumin Zhang , Gulinazi Yesitayi , Yunzhi Ling , Rifeng Gao , Yang Lyu , Wei Wei , Jiaran Shi , Yulin Li , Xiang Ma , Pingjin Gao , Junbo Ge , Aijun Sun

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引用次数: 0

Abstract

Background

Thoracic aortic dissection (TAD) is a highly lethal condition that is characterized by inflammatory cell infiltration. Recent evidence has indicated that Gasdermin D (GSDMD) plays an important role in vascular inflammation and degeneration. However, its effects on neutrophil extracellular trap formation and release (NETosis) during TAD remain unknown.

Methods

A TAD mouse model was generated using four-week-old male neutrophil-specific GSDMD-knockout mice (GSDMD^F/F; Elane^Cre) and dimethyl fumarate (DMF)-treated C57BL/6J mice by administering β-aminopropionitrile monofumarate (BAPN; 1 g/kg/day) in their drinking water for 4 weeks. Immunoprecipitation and immunofluorescence assays were performed to examine the role of the endoplasmic reticulum (ER) and its associated protein, caspase-12, in GSDMD-induced NETosis.

Results

GSDMD was elevated and co-localized primarily in neutrophils in the aortic tissues of patients with TAD and mice with BAPN-induced TAD. This was accompanied by increased NETosis. Neutrophil-specific GSDMD knockout and the NETosis inhibitor, GSK484, mitigated TAD development in mice. However, GSK484 did not provide additional therapeutic effects against TAD in the neutrophil-specific, GSDMD knockout mice. Mechanistically, ER stress promoted GSDMD cleavage by caspase-4/11, thereby inducing NETosis. Furthermore, caspase-12 exhibited non-redundant functions in the cleavage of GSDMD by caspase-4/11. The GSDMD inhibitor, DMF, partially prevented TAD development.

Conclusions

The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD.

Abstract Image

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Caspase-12在内质网应激反应中表现出非冗余功能，促进gsdmd介导的NETosis，导致胸主动脉夹层。

背景：胸主动脉夹层（TAD）是一种以炎症细胞浸润为特征的高致死率疾病。最近的证据表明，GSDMD在血管炎症和变性中起重要作用。然而，其对TAD期间中性粒细胞胞外陷阱形成和释放（NETosis）的影响尚不清楚。方法：采用4周龄雄性中性粒细胞特异性gsdmd敲除小鼠(GSDMDF/F；ElaneCre)和富马酸二甲酯（DMF）治疗C57BL/6J小鼠的方法是给药β-氨基丙腈单马酸酯(BAPN；1 g/kg/天)，持续4周。采用免疫沉淀法和免疫荧光法检测内质网（ER）及其相关蛋白caspase-12在gsdmd诱导的NETosis中的作用。结果：GSDMD在TAD患者和bapn诱导的TAD小鼠主动脉组织的中性粒细胞中升高并共定位。这伴随着NETosis的增加。中性粒细胞特异性GSDMD敲除和NETosis抑制剂GSK484可减轻小鼠TAD的发展。然而，GSK484对中性粒细胞特异性GSDMD敲除小鼠的TAD没有提供额外的治疗作用。机制上，内质网应激通过caspase-4/11促进GSDMD裂解，从而诱导NETosis。此外，caspase-12在caspase-4/11对GSDMD的切割中表现出非冗余功能。GSDMD抑制剂DMF部分阻止了TAD的发展。结论：内质网应激/GSDMD/NETosis信号通路为TAD的预防和治疗提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Research 医学-医学：内科

CiteScore

15.70

自引率

0.00%

发文量

195

审稿时长

14 days

期刊介绍： Translational Research (formerly The Journal of Laboratory and Clinical Medicine) delivers original investigations in the broad fields of laboratory, clinical, and public health research. Published monthly since 1915, it keeps readers up-to-date on significant biomedical research from all subspecialties of medicine.