Page 67 - 南京医科大学自然版

第45卷第8期 南京医科大学学报（自然科学版）
2025年8月 Journal of Nanjing Medical University（Natural Sciences） ·1123 ·

·基础研究·

Tyro3缺失加重LPS诱导的小鼠内毒素血症

汪 洁，方瑞琪，李 猛，杨 青，柏 惠，李晓宇 ，陈 琪
*
江苏省心血管病靶向干预研究重点实验室，南京医科大学基础医学院病理生理学系，江苏 南京 211166

［摘 要］ 目的：探究Tyro3蛋白酪氨酸激酶（Tyro3 protein tyrosine kinase，Tyro3）在内毒素血症中的作用及其分子调控机制。
方法：基于GEO数据库（GSE54514）分析脓毒症患者外周血Tyro3的表达谱；建立脂多糖（lipopolysaccharide，LPS）诱导（10 mg/kg，
腹腔注射）的内毒素血症小鼠模型，比较 Tyro3 全身基因敲除（Tyro3 ）与野生型（Tyro3 ）小鼠的疾病严重程度（临床评分、
-/-
+/+
96 h 生存率）、血浆炎症因子水平及肝脏急性炎症病理改变。同时，分离培养Tyro3 和Tyro3 小鼠的骨髓源性巨噬细胞，通过
-/-
+/+
LPS（100 ng/mL）刺激建立体外急性炎症模型，检测 LPS 诱导的核因子κB（nuclear factor kappa⁃B，NF⁃κB）炎症通路的激活情
况。结果：临床数据分析显示脓毒症患者外周血Tyro3表达显著下调。动物实验表明，与Tyro3 小鼠相比，Tyro3 小鼠表现出
-/-
+/+
更严重的脓毒症表现：临床评分显著降低，生存率显著下降，血浆炎症因子水平显著升高，肝脏急性炎性损伤更严重，炎症细胞
浸润更明显。体外实验研究发现，Tyro3 缺失导致巨噬细胞 NF⁃κB 通路过度激活，表现为 kappa B 抑制因子激酶（inhibitor of
kappa B kinase，IKK）、NF⁃κB p65 亚基的磷酸化水平增加及核因子κB 抑制蛋白α（NF⁃kappa⁃B inhibitor alpha，IκB⁃α）的降解
加速。使用蛋白S（protein S，Pros1）激活Tyro3可以有效抑制LPS诱导的NF⁃κB通路激活。结论：Tyro3通过负调控巨噬细胞NF⁃κB
信号通路减轻内毒素血症诱导的相关炎症反应及肝脏损伤，提示靶向Tyro3⁃NF⁃κB轴可能是内毒素血症治疗的潜在策略。
［关键词］ Tyro3；内毒素血症；巨噬细胞；炎症；NF⁃κB
［中图分类号］ R392.32 ［文献标志码］ A ［文章编号］ 1007⁃4368（2025）08⁃1123⁃09
doi：10.7655/NYDXBNSN250607

Deletion of Tyro3 exacerbates LPS⁃induced endotoxemia in mice

*
WANG Jie，FANG Ruiqi，LI Meng，YANG Qing，BAI Hui，LI Xiaoyu ，CHEN Qi
Key Laboratory of Targeted Intervention of Cardiovascular Disease，Department of Pathophysiology，School of Basic
Medicine，Nanjing Medical University，Nanjing 211166，China

［Abstract］ Objective：To investigate the role of Tyro3 protein tyrosine kinase（Tyro3）in the pathogenesis of endotoxemia and its
underlying molecular mechanisms. Methods：The expression profile of Tyro3 in peripheral blood from septic patients was analyzed
using the GEO database（GSE54514）. An endotoxemia mouse model was established by intraperitoneal injection of lipopolysaccharide
（LPS，10 mg/kg）. Disease severity⁃including clinical scores，96⁃hour survival rates，plasma inflammatory cytokine levels，and acute
hepatic inflammatory pathology⁃was evaluated and compared between systemic Tyro3 knockout（Tyro3 ）and wild⁃type（Tyro3 ）
+/+
-/-
-/-
+/+
mice. Additionally，bone marrow⁃derived macrophages（BMDMs）were isolated from Tyro3 and Tyro3 mice and stimulated with LPS
（100 ng/mL）to establish an in vitro acute inflammation model. Activation of the nuclear factor kappa⁃B（NF⁃κB）signaling pathway
was assessed. Results：Clinical data analysis revealed a significant downregulation of Tyro3 expression in the peripheral blood of septic
patients. In vivo experiments demonstrated that Tyro3 -/- mice exhibited exacerbated endotoxemia compared to Tyro3 +/+ mice，as
evidenced by significantly worsened clinical scores，reduced survival rates，elevated plasma inflammatory cytokine levels，more severe
acute liver injury，and increased inflammatory cell infiltration. In vitro studies showed that Tyro3 deficiency led to hyperactivation of
the NF⁃κB pathway in macrophages，characterized by enhanced phosphorylation of inhibitor of kappa B kinase（IKK）and the p65
subunit of NF⁃κB，along with accelerated degradation of NF⁃kappa⁃B inhibitor alpha（IκB⁃α）. Pharmacological activation of Tyro3
using protein S（Pros1）effectively suppresses NF ⁃ κB pathway activation. Conclusion：Tyro3 attenuates endotoxemia ⁃ induced
inflammatory responses and hepatic injury by negatively regulating the NF ⁃κB signaling pathway in macrophages，suggesting that

［基金项目］ 国家自然科学基金（82030012，81670263）；江苏高等学校自然科学基金（24KJA310003）
通信作者（Corresponding author），E⁃mail：xyli@njmu.edu.cn（ORCID：0000⁃0002⁃2659⁃7680）
∗