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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,30]]},"abstract":"<jats:p>\n                    Colorectal cancer and Crohn\u2019s 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 (\n                    <jats:italic>Irp2<\/jats:italic>\n                    ), globally (\n                    <jats:italic>\n                      Irp2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) or myeloid cell lineage (\n                    <jats:italic>Lysozyme 2 promoter-driven, LysM<\/jats:italic>\n                    )-specifically (\n                    <jats:italic>\n                      Irp2\n                      <jats:sup>\u0394LysM<\/jats:sup>\n                      )\n                    <\/jats:italic>\n                    , are highly susceptible to liver abscesses when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that\n                    <jats:italic>Irp2<\/jats:italic>\n                    is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In\n                    <jats:italic>Irp2<\/jats:italic>\n                    -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\u2019s disease and through bioinformatic searches in databases from Crohn\u2019s 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2321929121","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T13:38:01Z","timestamp":1721828281000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages"],"prefix":"10.1073","volume":"121","author":[{"given":"Chen","family":"Cheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, People\u2019s Republic of 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