Wang Huitong, Su Zhaojie, Qian Yunyun, Shi Baojie, Li Hao, An Wenbin, Xiao Yi, Qiu Cheng, Guo Zhixiang, Zhong Jianfa, Wu Xia, Chen Jiajia, Wang Ying, Zeng Wei, Zhan Linghui, Wang Jie
Department of Organ Transplantation, School of Medicine, Organ Transplantation Clinical Medical Center of Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China.
Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Organ Transplantation Institute of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China.
Mol Biomed. 2024 Dec 12;5(1):68. doi: 10.1186/s43556-024-00227-6.
The liver plays a crucial role in the immune response during endotoxemia and is one of the critical targets for sepsis-related injuries. As a secretory factor involved in inflammation, pentraxin-3 (PTX3) has been demonstrated to regulate hepatic homeostasis; however, the relationship between PTX3 and cell crosstalk between immune cells and hepatocytes in the liver remains incompletely understood. In this study, we revealed that, compared with WT mice, Ptx3 mice with lipopolysaccharide (LPS)-induced endotoxemia exhibited alleviated liver damage, with reduced serum alanine transaminase and aspartate transaminase levels and an improved survival rate. Mechanistically, RNA-Seq and western blot results revealed that Ptx3 knockdown in hepatocytes increased the expression of Tfrc and Ccl20; consequently, Ptx3 deficiency regulated LPS-induced hepatocyte ferroptosis via increased mitochondrial reactive oxygen species and Fe and recruited more macrophages by CCL20/CCR6 axis to be involved in inflammation and the clearance of harmful substances. Moreover, western blot and immunofluorescence staining confirmed that the NF-κB signaling pathway was upregulated upon LPS treatment in Ptx3-knockdown macrophages, promoting phagocytosis and polarization toward M1 macrophages. Collectively, our findings show that the absence of Ptx3 can ameliorate sepsis-induced liver injury by regulating hepatocyte ferroptosis and promote the recruitment and polarization of M1 macrophages. These findings offer a key basis for the development of effective treatments for acute infections.
肝脏在内毒素血症期间的免疫反应中起关键作用，是脓毒症相关损伤的关键靶点之一。作为一种参与炎症反应的分泌因子，五聚体蛋白3（PTX3）已被证明可调节肝脏内环境稳态；然而，PTX3与肝脏中免疫细胞和肝细胞之间的细胞间相互作用的关系仍未完全明确。在本研究中，我们发现，与野生型小鼠相比，脂多糖（LPS）诱导的内毒素血症的Ptx3基因敲除小鼠肝损伤减轻，血清丙氨酸转氨酶和天冬氨酸转氨酶水平降低，存活率提高。机制上，RNA测序和蛋白质印迹结果显示，肝细胞中Ptx3基因敲低增加了Tfrc和Ccl20的表达；因此，Ptx3缺乏通过增加线粒体活性氧和铁来调节LPS诱导的肝细胞铁死亡，并通过CCL20/CCR6轴募集更多巨噬细胞参与炎症反应和有害物质清除。此外，蛋白质印迹和免疫荧光染色证实，在Ptx3基因敲除的巨噬细胞中，LPS处理后NF-κB信号通路上调，促进吞噬作用并向M1巨噬细胞极化。总的来说，我们的研究结果表明，Ptx3缺失可通过调节肝细胞铁死亡改善脓毒症诱导的肝损伤，并促进M1巨噬细胞的募集和极化。这些发现为开发有效的急性感染治疗方法提供了关键依据。
