Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

The interplay between pathogens and host immunity is governed by complex epigenetic and transcriptional networks. While ID3 (Inhibitor of Differentiation 3) modulates various immune cell functions, its role in macrophage-mediated defense during infection remains poorly understood. Here, we found that Salmonella (STM) infection induces the deacetylation of histone H2BK16, which mediated by HDAC1/3, and leading to the transcriptional silencing of Id3 . Loss- and gain-of-function experiments demonstrate that ID3 confers potent antibacterial activity to macrophages. Deficiency of ID3 attenuates the inflammatory and antimicrobial immune response of macrophages. Mechanistically, ID3 maintains Z-DNA binding protein 1 (ZBP1) expression by sequestering the transcription factor E2A, thereby relieving E2A-mediated transcriptional repression. In vivo, myeloid-specific Id3 deficiency exacerbates bacterial burdens and pathological damage in mice. Treatment with the HDAC inhibitor MS-275 restores the H2BK16ac-ID3 axis and ameliorates systemic STM infection. These findings unveil an infection-associated epigenetic circuit governing ID3 expression and macrophage antimicrobial defense, revealing potential therapeutic targets for anti-infective therapy.