Department of Cardiovascular, The First Hospital of Nanchang, Nanchang, Jiangxi, China.
Department of Cardiovascular, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China.
Cell Biol Int. 2022 Feb;46(2):265-277. doi: 10.1002/cbin.11728. Epub 2021 Dec 2.
Forkhead box protein P1 (Foxp1) is a kind of tumor suppressor gene, and the role of Foxp1 in the macrophages of myocardial infarction (MI) has not been studied yet. Here, we verified the role of the transcription factor high mobility group box 1 (HMGB1) and its target gene Foxp1 in the inflammatory response. In this study, the key genes HMGB1 and Foxp1 in the macrophages of mouse MI model were screened out through single-cell transcriptome analysis of GSE136088 (GEO database). In vitro experiment indicated that hypoxia induced the inflammatory response in RAW264.7 macrophages, promoted the secretion of inflammatory factors (tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and IL-1β) and the activation of NLRP3 inflammasome (NLRP3, ASC, and pro-caspase-1). Meanwhile, HMGB1 increased while Foxp1 decreased in hypoxia-treated RAW264.7 macrophages. HMGB1 bound to the upstream promoter region of Foxp1 as demonstrated by the dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) and agarose gel electrophoresis. As a transcription factor, HMGB1 regulated Foxp1 expression. The secretion of inflammatory factors and the expression of NLRP3 inflammasome protein were changed when the expression of HMGB1 and Foxp1 was regulated in the hypoxia-treated RAW264.7 macrophages. This study verified that HMGB1 could aggravate the hypoxia-treated inflammatory response of macrophages through downregulating Foxp1, which not only provides evidence to support the role of HMGB1/Foxp1 in macrophages but also offers another angle for the treatment of MI.
叉头框蛋白 P1（Foxp1）是一种肿瘤抑制基因，但其在心肌梗死（MI）巨噬细胞中的作用尚未研究。本研究通过 GSE136088（GEO 数据库）单细胞转录组分析，验证了转录因子高迁移率族蛋白 B1（HMGB1）及其靶基因 Foxp1 在炎症反应中的作用。本研究通过 GSE136088（GEO 数据库）单细胞转录组分析，筛选出小鼠 MI 模型中巨噬细胞的关键基因 HMGB1 和 Foxp1。体外实验表明，缺氧诱导 RAW264.7 巨噬细胞炎症反应，促进炎症因子（肿瘤坏死因子-α [TNF-α]、白细胞介素-6 [IL-6]和白细胞介素-1β）和 NLRP3 炎性体（NLRP3、ASC 和前胱天蛋白酶-1）的激活。同时，缺氧处理 RAW264.7 巨噬细胞中 HMGB1 增加而 Foxp1 减少。双荧光素酶报告基因检测、染色质免疫沉淀（ChIP）-定量聚合酶链反应（qPCR）和琼脂糖凝胶电泳证实 HMGB1 与 Foxp1 的上游启动子区结合。作为一种转录因子，HMGB1 调节 Foxp1 的表达。调节缺氧处理 RAW264.7 巨噬细胞中 HMGB1 和 Foxp1 的表达，可改变炎症因子的分泌和 NLRP3 炎性体蛋白的表达。本研究证实 HMGB1 通过下调 Foxp1 加重缺氧处理的巨噬细胞炎症反应，不仅为 HMGB1/Foxp1 在巨噬细胞中的作用提供了证据支持，也为 MI 的治疗提供了另一个角度。
