FOXM1 Enhances Transcription of S1PR1 and Promotes Pro-Inflammatory Activation of Kupffer Cells in Alcoholic Hepatitis

Following the bioinformatics predictions, this investigation delves into the function of FOXM1 in the phenotype of macrophages and inflammatory responses in alcoholic hepatitis (AH). A mouse model of AH was generated using the Lieber-DeCarli method, and mouse Kupffer cells (KCs) were treated with lipopolysaccharide and ethanol. Expression of FOXM1 and S1PR1 in mouse liver tissues or KCs was determined using RT-qPCR, immunofluorescence, or western blot assays. Loss- or gain-of-function assays of FOXM1 and S1PR1 were performed, followed by histopathological staining of the liver tissues, examination of the inflammatory cytokines, and assessment of macrophage phenotype. FOXM1 exhibited heightened expression in the mouse liver tissues and KCs in AH models. Silencing FOXM1 reduced pathological injury, hepatic steatosis, alanine aminotransferase and aspartate aminotransferase levels, inflammatory cytokine production, and pro-inflammatory (M1) polarization markers of macrophages. This condition also alleviated M1 polarization of KCs <i>in vitro</i>. FOXM1 promoted transcription and expression of S1PR1 by binding to its promoter. The additional upregulation of S1PR1, in the presence of FOXM1, rescued M1 skewing of macrophages both <i>in vitro</i> and <i>in vivo</i>, thus aggravating inflammatory responses. This study identifies that FOXM1-mediated transcriptional upregulation of S1PR1 promotes pro-inflammatory activation of macrophages and augments liver injury in AH.