A Conserved Chromatin-Driven Checkpoint Defines Late Macrophage Maturation Independent of Tissue Specialization

Authors

Pasajlic, D., Plaschka, M., Assen, F. P., Kusienicka, A., Shaw, L. E., Traxler, P., Mann, U., Petrovic, M., Bogdanovic, J., Weninger, W., Decker, T., Halbritter, F., Farlik, M.

Abstract

Macrophage identity is widely viewed as a product of ontogeny and tissue-specific imprinting. Here, we identify a conserved, chromatin-driven maturation checkpoint that operates independently of initial lineage commitment and broadly across tissue contexts. Using long-term bone marrow-derived macrophage cultures, we uncover a late-stage transition characterized by coordinated transcriptional an epigenomic remodeling. Integration with in vivo developmental, tissue-resident, and monocyte repopulation datasets demonstrates that this program is conserved across ontogenies, tissues, species, and experimental systems, revealing a previously unrecognized stage of macrophage maturation. Functionally, late maturation preserves core macrophage activities while promoting lysosomal expansion and fundamentally rewiring innate immune responsiveness. Mature macrophages display enhanced stimulus-specific responses to interferons and microbial danger signals, coupled to increased metabolic and inflammatory competence while restricting interferon-induced transcriptional memory. Together, our findings identify late macrophage maturation as a conserved regulatory checkpoint that reprograms the logic of innate immune responsiveness through chromatin remodeling shaping innate immune function.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Jul 2026.

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