A Polyamine-mediated Posttranslational Modification Required for Macrophage Tissue Residency [Ribo-seq]

Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris. During tissue damage, however, bone marrow-derived monocytes enter tissue sites and differentiate into RTM, repairing the tissue and replenishing macrophages in the niche. Universal cell-intrinsic mechanisms that control the monocyte to RTM transition remain elusive. We investigated mice with myeloid cell deletions in deoxyhypusine synthase (DHPS), an enzyme that mediates the polyamine-dependent hypusine modification of the translation factor eIF5A, and found that DHPS is required for cell adhesion and signaling programs critical for RTMs. Without DHPS expression, immature tissue macrophages form, but RTM and associated homeostatic functions are lost. Thus, the polyamine-hypusine pathway is a global, tissue-agnostic program driving the differentiation trajectory of monocyte-derived macrophages into RTM.