Preprint Club - Immunology (@preprintclub.bsky.social)

Today at #PreprintHub2, Amitava from Vienna will present [email protected] ’s preprint, “O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration”, from the Bart Everts lab 💯✅ www.biorxiv.org/content/10.6...

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O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration The metabolic requirements for macrophage IL-4 polarization remain contentious, while immunometabolic studies of tissue resident macrophages are still sparse. Hexosamine biosynthesis has gained attention regarding its immune regulatory potential via downstream O-GlcNAcylation. Here we identify protein O-GlcNAcylation as a requirement for IL-4 polarization in vitro and proliferative expansion in vivo during cytokine challenge or infection. We further show that O-GlcNAcylation is critical for controlling tissue residency. By enforcing metabolic and cell cycle quiescence during differentiation, O-GlcNAcylation is needed for adult monocytes to establish a long-live residency program. In this context, its absence leads to perpetual DNA vulnerability and damage via reactive oxygen species, resulting in a senescent-like state poised for cell death. Conversely, long-lived populations instead require O-GlcNAcylation for self-renewal and inflammatory expansion. Our findings altogether suggest O-GlcNAcylation, fueled by hexosamine biosynthesis, serves as a central metabolic rheostat for resident macrophage formation and maintenance during homeostasis and disease. ### Competing Interest Statement The authors have declared no competing interest. Dutch Research Council, https://ror.org/04jsz6e67, 91614087 Wellcome Trust, 219530 Taighde Éireann - Research Ireland, https://ror.org/010t7sr36, 22/PATH-S/10649 https://www.biorxiv.org/content/10.64898/2026.01.05.697622v1