The transition from monocyte to tissue-resident macrophage requires DHPS

作者：Gustavo Carrizo, Pianpian Lin, Seung Hyun Lee, Kevin Shenderov, Camille Blériot, Minsun Cha, Lena Schimmelpfennig, Zhen Shen, Nikki van Teijlingen Bakker, Katarzyna M. Grzes, Beth Kelly, Niloufar Safinia, Kate L. Schole, Yaarub Musa, Gerhard Mittler, Yoh Zen, Edward J. Pearce, Edward J. Pearce, Florent Ginhoux, David E. Sanin, Daniel J. Puleston, Erika L. Pearce, Erika L. Pearce · 发表于：Nature · 年份：2026 · DOI：10.1038/s41586-025-09972-2 · 被引用次数：3 · 研究领域：Polyamine Metabolism and Applications、Aldose Reductase and Taurine、Microbial metabolism and enzyme function

Abstract Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris 1–6 . During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche 1 . The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive 3 . Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A 5,7 , is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS ( Dhps -ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue m...