Activation of α7 Nicotinic Acetylcholine Receptors Inhibits Hepatic Necroptosis and Ameliorates Acute Liver Injury in Mice.

IF 9.1 1区医学 Q1 ANESTHESIOLOGY Anesthesiology Pub Date : 2024-12-01 DOI:10.1097/ALN.0000000000005206

Fang-Fang Xu, Zi-Chen Li, Wen-Jing Zhang, Qiao Li, Dong-Jie Li, Hong-Bo Meng, Fu-Ming Shen, Hui Fu

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Abstract

Background: Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms.

Methods: Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Stinggt/gt) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed.

Results: The expression of α7nAChR in liver tissue was increased in LPS/D-Gal-induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR.

Conclusions: The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal-induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.

Editor’s perspective:

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激活α7烟碱乙酰胆碱受体可抑制小鼠肝坏死并改善急性肝损伤。

背景：急性肝损伤（ALI）是一种以严重肝功能障碍为特征的疾病，由大量免疫细胞浸润和广泛的细胞死亡引起，死亡率很高。以往的研究表明，α7 尼古丁乙酰胆碱受体（α7nAChR）在各种肝脏疾病中起着至关重要的作用。本研究的假设是激活α7nAChR可以缓解ALI并研究其可能的机制：方法：通过腹腔注射脂多糖（LPS）/D-半乳糖胺（D-Gal）诱导野生型（WT）、α7nAChR基因敲除（α7nAChR -/-）和Sting基因突变（Stinggt/gt）小鼠发生ALI，并在有或无药理学选择性α7nAChR激动剂（PNU-282987）的情况下进行实验。评估了α7nAChR对ALI期间肝损伤、炎症反应、线粒体损伤、坏死和免疫细胞浸润的影响：结果：LPS/D-Gal诱导的ALI小鼠肝组织中α7nAChR的表达增加。与年龄匹配的 WT 小鼠相比，α7nAChR 缺乏降低了小鼠的存活率，加剧了肝损伤，并伴有炎症反应和氧化应激的增强，加重了肝线粒体损伤和坏死。相反，PNU-282987 对 α7nAChR 的药理激活却显示出相反的趋势。此外，PNU-282987 还能显著降低浸润的单核细胞衍生巨噬细胞（CD45+CD11bhiF4/80int）、M1 巨噬细胞（CD45+CD11b+F4/80+CD86 hiCD163low）和 Ly6Chi 单核细胞（CD45+CD11bhiF4/80+CD86 hiCD163low）的比例、Ly6Chi单核细胞（CD45+CD11b+MHCⅡ lowLy6C hi），但在LPS/D-Gal造成的肝损伤组织中增加了常驻Kupffer细胞（CD45+CD11bintF4/80 hiTIM4 hi）。有趣的是，在LPS/D-Gal刺激下，α7nAChR缺陷促进了STING信号通路，而PNU-282987治疗则显著阻止了其激活。最后，研究发现，Sting突变取消了激活α7nAChR对肝损伤的保护作用：我们的研究表明，激活α7nAChR可抑制肝脏炎症和坏死，从而保护肝脏免受LPS/D-Gal诱导的ALI损伤，这可能是通过调节免疫细胞浸润和抑制STING信号通路实现的。

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来源期刊

Anesthesiology 医学-麻醉学

CiteScore

10.40

自引率

5.70%

发文量

542

审稿时长

3-6 weeks

期刊介绍： With its establishment in 1940, Anesthesiology has emerged as a prominent leader in the field of anesthesiology, encompassing perioperative, critical care, and pain medicine. As the esteemed journal of the American Society of Anesthesiologists, Anesthesiology operates independently with full editorial freedom. Its distinguished Editorial Board, comprising renowned professionals from across the globe, drives the advancement of the specialty by presenting innovative research through immediate open access to select articles and granting free access to all published articles after a six-month period. Furthermore, Anesthesiology actively promotes groundbreaking studies through an influential press release program. The journal's unwavering commitment lies in the dissemination of exemplary work that enhances clinical practice and revolutionizes the practice of medicine within our discipline.