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败血症诱导的NET形成需要MYD88,但独立于GSDMD和PAD4

Hanna Englert¹, Chandini Rangaswamy¹, Giuliano A Kullik¹

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

|January 8, 2025

概括

中性细胞细胞外陷 (NETs) 对于宿主防御至关重要,但可以导致致命的血管封闭. 这项研究揭示了在败血症和中性恋期间调节NET形成的独特途径,独立于PAD4和GSDMD.

科学领域:

免疫学免疫学免疫学
细胞生物学细胞生物学
病理学病理学病理学

背景情况:

中性粒细胞释放中性粒细胞外细胞陷 (NETs),对于对抗病原体至关重要.
失调的NET形成可能导致严重的疾病,如败血症引起的血管封闭.
正在调查NET形成的关键调节者,包括MYD88,PAD4和GSDMD.

研究的目的:

为了比较骨髓分化因子88 (MYD88),基氨酸减弱酶4 (PAD4) 和气皮素D (GSDMD) 在体内NET形成中的作用.
调查在败血症和中性恋期间NET形成的刺激依赖调节.
确定PAD4和GSDMD是否对特定小鼠模型中NET介导的致死性至关重要.

主要方法:

使用了Dnase1和Dnase1l3 (D1/D1l3-/-) 遗传缺陷的小鼠模型,结合Myd88,Pad4或Gsdmd的缺陷.
通过脂多糖 (LPS) /E.诱导NET形成. 大肠杆菌挑战 (败血症模型) 或颗粒细胞殖民地刺激因子 (G-CSF) (中性恋模型).
评估了NET形成,血管封闭,血栓,器官损伤和死亡率.

主要成果:

在败血症期间,Myd88缺乏对致命的NET形成有保护作用,但对中性恋没有保护作用.
缺乏Gsdmd和Pad4的小鼠形成了NET,并在败血症期间经历了致命的血管封闭,类似于对照小鼠.
药理上GSDMD抑制和Pad4/Gsdmd缺乏症并没有防止在中性恋期间形成NET或致死性.

结论:

在实验性败血症和中性恋期间的NET形成是由不同的,依赖刺激的途径调节的.
在所有实验条件下,正规的PAD4和GSDMD可能对NET形成或相关的致命性不至关重要.
研究结果表明,通过区分刺激特异性调节机制,对NET介导疾病提出了新的治疗点.

关键词:

GSDMDMD的总体发展目标是什么在PAD4中使用PAD4.免疫血栓形成免疫血栓形成这是一种炎症炎症炎症炎症.中性粒细胞外细胞陷血管生物学血管生物学

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