Wang Yane, Liu Zhimin, Zhang Mengli, Yu Bo, Ai Fen
Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Microbiol. 2023 Mar 7;14:1117285. doi: 10.3389/fmicb.2023.1117285. eCollection 2023.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) modulates the inflammatory immune response and organ dysfunction, which are closely implicated in sepsis pathogenesis and progression. This study aimed to explore the role of MALT1 in sepsis-induced organ injury, immune cell dysregulation, and inflammatory storms.
Septic mice were constructed by intraperitoneal injection of lipopolysaccharide, followed by overexpression or knockdown of MALT1 by tail vein injection of the corresponding lentivirus. Mouse naïve CD4 T cells and bone marrow-derived macrophages were treated with MALT1 overexpression/knockdown lentivirus plus lipopolysaccharide.
In the lungs, livers, and kidneys of septic mice, MALT1 overexpression exaggerated their injuries, as shown by hematoxylin and eosin staining (all < 0.05), elevated cell apoptosis, as reflected by the TUNEL assay and cleaved caspase-3 expression ( < 0.05 in the lungs and kidneys), and promoted macrophage infiltration, as illustrated by CD68 immunofluorescence ( < 0.05 in the lungs and kidneys). Meanwhile, in the blood, MALT1 overexpression reduced T-helper (Th)1/Th2 cells, increased Th17/regulatory T-cell ratios (both < 0.05), promoted systematic inflammation, as revealed by tumor necrosis factor-α, interleukin-6, interleukin-1β, and C-reactive protein (all < 0.05), elevated oxidative stress, as shown by nitric oxide ( < 0.05), superoxide dismutase, and malondialdehyde ( < 0.05), and enhanced liver and kidney dysfunction, as revealed by an automatic animal biochemistry analyzer (all < 0.05 except for aspartate aminotransferase). However, MALT1 knockdown exerted the opposite effect as MALT1 overexpression. experiments revealed that MALT1 overexpression promoted the polarization of M1 macrophages and naïve CD4 T cells toward Th2 and Th17 cells (all < 0.05), while MALT1 knockdown attenuated these effects (all < 0.05). Mechanistically, MALT1 positively regulated the nuclear factor-κB (NF-κB) pathway both and ( < 0.05).
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 amplifies multiple organ injury, inflammation, oxidative stress, and imbalance of macrophages and CD4 T cells by activating the NF-κB pathway in sepsis.
黏膜相关淋巴组织淋巴瘤易位蛋白1（MALT1）调节炎症免疫反应和器官功能障碍，这与脓毒症的发病机制和进展密切相关。本研究旨在探讨MALT1在脓毒症诱导的器官损伤、免疫细胞失调和炎症风暴中的作用。
通过腹腔注射脂多糖构建脓毒症小鼠模型，随后通过尾静脉注射相应的慢病毒对MALT1进行过表达或敲低。用MALT1过表达/敲低慢病毒加脂多糖处理小鼠初始CD4 T细胞和骨髓来源的巨噬细胞。
在脓毒症小鼠的肺、肝和肾中，MALT1过表达加剧了它们的损伤，苏木精和伊红染色显示（均P<0.05），TUNEL检测和裂解的半胱天冬酶-3表达反映细胞凋亡增加（肺和肾中P<0.05），CD68免疫荧光显示促进巨噬细胞浸润（肺和肾中P<0.05）。同时，在血液中，MALT1过表达减少辅助性T（Th）1/Th2细胞，增加Th17/调节性T细胞比例（均P<0.05），肿瘤坏死因子-α、白细胞介素-6、白细胞介素-1β和C反应蛋白显示促进全身炎症（均P<0.05），一氧化氮显示氧化应激升高（P<0.05）、超氧化物歧化酶和丙二醛（P<0.05），自动动物生化分析仪显示肝和肾功能障碍增强（除天冬氨酸转氨酶外均P<0.05）。然而，MALT1敲低产生与MALT1过表达相反的效果。实验显示，MALT1过表达促进M1巨噬细胞和初始CD4 T细胞向Th2和Th17细胞极化（均P<0.05），而MALT1敲低减弱了这些作用（均P<0.05）。机制上，MALT1在体内和体外均正向调节核因子-κB（NF-κB）通路（P<0.05）。
黏膜相关淋巴组织淋巴瘤易位蛋白1通过在脓毒症中激活NF-κB通路放大多器官损伤、炎症、氧化应激以及巨噬细胞和CD4 T细胞的失衡。
