HMGB1/Foxp1 regulates hypoxia-induced inflammatory response in macrophages

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.