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通过抑制中性粒细胞外细胞陷的产生,APOE可以防止严重的结核菌感染

Dong Liu¹, Dat Mai¹, Ana N Jahn¹

¹Center for Global Infectious Disease Research, Seattle Children's Research Institute; Seattle, WA 98109, USA.

bioRxiv : the preprint server for biology

|November 28, 2024

概括

中性细胞外细胞陷 (NETs) 通过促进炎症,在易受感染的小鼠中驱动严重的结核病. 抑制NET形成或关键炎症途径显著改善结核病的结果.

科学领域:

免疫学免疫学免疫学
传染性疾病传染性疾病
心血管研究研究心血管研究

背景情况:

中性粒细胞在人类结核肺部丰富,但在典型的小鼠模型中很少.
在高胆固醇饮食中的Apoe-/-小鼠模仿人类中性粒细胞对Mycobacterium tuberculosis (Mtb) 的反应.

研究的目的:

研究中性粒细胞和中性粒细胞外细胞陷 (NETs) 在严重结核病的小鼠模型中的作用.
为了阐明驱动中性粒细胞驱动的肺病理在Mycobacterium结核病感染驱动的机制.

主要方法:

在高胆固醇饮食中使用的Apoe-/-小鼠感染了Mtb.
使用中性粒细胞枯竭,pDC枯竭,I型干扰素信号阻断,以及LTB4受体对抗剂.
研究了阻断丁氨酸脱胺酶4 (PAD4) 对NET形成和疾病结局的影响.

主要成果:

中性粒细胞枯竭,pDC枯竭或I型干扰素阻塞改善了结核病的结果.
LTB4和12-HETE水平升高,而LTB4受体阻断改善了结果.
阻断PAD4降低了NETs,并在Apoe-/-HC小鼠中完全逆转了过敏性.

结论:

一个涉及NETs,pDCs和I型干扰子的前循环在这个模型中驱动严重的结核病.
NETs在结核病发病过程中起着因果作用,使PAD4成为潜在的治疗点.

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