Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Department of Bio-Signal Analysis, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan.
Department of Microbiology and Immunology, Yamaguchi University, School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan.
Commun Biol. 2024 May 7;7(1):527. doi: 10.1038/s42003-024-06099-4.
Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.
巨噬细胞是先天免疫系统中具有多种功能的细胞，可通过改变其促炎或抗炎特性来发挥作用。它们的失调会导致炎症性疾病，如炎症性肠病。我们表明，巨噬细胞特异性上调时钟输出基因和转录因子 E4BP4 可降低小鼠结肠炎的严重程度。对巨噬细胞的 RNA 测序和单细胞分析表明，E4BP4 的表达增加导致抗炎基因的总体表达增加，包括 Il4ra，同时促炎基因的表达减少。相比之下，巨噬细胞中 E4BP4 的敲除会导致促炎基因的表达增加和抗炎基因的表达减少。ChIP-seq 和 ATAC-seq 分析进一步将 Il4ra 鉴定为 E4BP4 的靶标，E4BP4 可驱动巨噬细胞中的抗炎极化。总之，这些结果揭示了 E4BP4 在调节巨噬细胞炎症表型和解决炎症性肠病方面的关键作用。
