Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ...

Chronic alcohol use causes pancytopenia and diminished immune responses against pathogens. However, it remains unclear whether chronic alcohol consumption directly induces inflammation in human hemato...

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