Colorectal cancer and Crohn’s disease patients develop pyogenic liver abscesses due to failures of immune cells to fight off bacterial infections. Here, we show that mice lacking iron regulatory protein 2 ( Irp2 ), globally ( Irp2 −/− ) or myeloid cell lineage ( Lysozyme 2 promoter-driven, LysM )-specifically ( Irp2 ΔLysM ) , are highly susceptible to liver abscesses when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that Irp2 is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In Irp2 -deficient liver tissue or macrophages, the nuclear location of transcription factor EB (Tfeb) was remarkably reduced, leading to the downregulation of Tfeb target genes that encode critical components for lysosomal biogenesis. Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn’s disease and through bioinformatic searches in databases from Crohn’s disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.

中文翻译：

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铁调节蛋白 2 通过保护巨噬细胞中的溶酶体功能促进抗菌免疫


由于免疫细胞无法抵抗细菌感染，结直肠癌和克罗恩病患者会出现化脓性肝脓肿。在这里，我们展示了缺乏铁调节蛋白 2 的小鼠（ IRP2 ），全局（ IRP2 −/− ）或骨髓细胞谱系（溶菌酶 2 启动子驱动，LysM ）-具体来说 （ IRP2 ΔLysM ） ，当肠道组织受到右旋糖酐硫酸钠治疗损伤时，极易发生肝脓肿。进一步的研究表明IRP2是溶酶体酸化和生物发生所必需的，这两者对于细菌清除至关重要。在IRP2 -肝组织或巨噬细胞缺陷，转录因子EB（Tfeb）的核位置显着减少，导致编码溶酶体生物合成关键成分的Tfeb靶基因下调。 Tfeb 的错误定位可通过缺氧诱导因子 2 抑制剂 PT2385 逆转，并且独立地通过抑制乳酸产生逆转。这些实验结果在克罗恩病患者中得到了临床证实，并通过克罗恩病或溃疡性结肠炎活组织检查的数据库中的生物信息搜索证实了 IRP2 和转录因子 EB (TFEB) 依赖性溶酶体基因表达的丧失。总体而言，我们的研究强调了 Irp2 支持 Tfeb 核转位和溶酶体功能、保留巨噬细胞抗菌活性并在肠道炎症期间保护肝脏免受细菌入侵的机制。