Foxj2 Attenuates LPS-Induced Inflammatory Response in Macrophages.

BACKGROUND: Macrophages are central to innate immune responses and are crucial in maintaining homeostasis and managing inflammatory diseases. Forkhead box J2 (Foxj2) is a member of the forkhead/hepatocyte nuclear factor 3 transcription factor family and is essential for multiple biological functions. However, the involvement of Foxj2 in the inflammatory process in macrophages remains unclear. OBJECTIVE: The present study aimed to explore the role of Foxj2 in the inflammatory processes of macrophages activated through lipopolysaccharide (LPS) stimulation. METHODS: The modulation of Foxj2 expression in macrophages in response to LPS stimulation was investigated via reverse-transcription quantitative (RT-q) PCR, Western blot, and immunofluorescence staining assays. Macrophages were infected with adenovirus vectors to upregulate the expression of the Foxj2 gene. Luciferase reporter gene assay and chromatin immunoprecipitation (ChIP)-PCR analysis were used to determine the regulatory relationship between Foxj2 and Tak1 (transforming growth factor-β-activated kinase 1). RESULTS: LPS stimulation of peritoneal macrophages led to a significant decrease in Foxj2 expression. In addition, LPS treatment led to Foxj2 depletion in several mouse tissues, including the heart, liver, spleen, lungs, kidneys, adipose tissue, blood vessels, and peritoneal macrophages. Furthermore, Foxj2 overexpression ameliorated the mRNA expression of TNF, IL-1β, IL-6, IL-12, IFN-stimulated gene 15, and IFN-β in macrophages treated with LPS. Additionally, Foxj2 overexpression attenuated phosphorylation of Stat1, p65, Erk1/2, Jnk, and p38. Subsequent experiments confirmed the binding of Foxj2 to the promoter region of Tak1, led to the suppression of Tak1's transcriptional activity. Moreover, a reduction in Foxj2 levels was observed during the pathological processes of numerous diseases characterized by inflammation, including high-fat diet (HFD)-induced obesity, HFD-induced nonalcoholic fatty liver disease (NAFLD), doxorubicin-induced cardiomyopathy, acute myocardial infarction (AMI) and D-galactose induced aging conditions. CONCLUSION: The present findings indicated that Foxj2 is crucial in mitigating macrophage inflammation induced by LPS and might be considered a target for treating sepsis and other inflammatory diseases.