Histone demethylase JMJD2D promotes macrophage IL-12b expression and contributes to host defense against Listeria monocytogenes infection

Abstract

Listeria monocytogenes ( L. monocytogenes ) is an intracellular bacterial pathogen that requires coordinated innate and adaptive immune responses for effective clearance. However, the epigenetic mechanisms governing host defense against L. monocytogenes remain poorly understood. JMJD2D-deficient mice and wild-type littermates were infected with L. monocytogenes to assess host susceptibility, bacterial burdens, tissue damage, and survival. Bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs) were isolated for in vitro infection assays. Molecular mechanisms were investigated in macrophages using siRNA-mediated knockdown, luciferase reporter assays, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). JMJD2D deficiency markedly increased host susceptibility to L. monocytogenes infection, resulting in elevated bacterial burdens, aggravated tissue damage, and reduced survival. Mechanistically, JMJD2D promoted NOD2-associated innate sensing and enhanced IL-12b transcription, accompanied by reduced H3K9me3 enrichment at the IL-12b promoter and cooperation with c-Rel. JMJD2D deficiency was associated with reduced IL-12p70 secretion and impaired macrophage bactericidal activity. Furthermore, JMJD2D contributed to coordinated macrophage and CD8 + T cell responses, as JMJD2D promoted IL-12b expression and IL-12p70 production in macrophages, while IFNγ enhanced macrophage IL-12b expression through the IFNGR2-JAK2-STAT1 pathway. Notably, the catalytic activity of JMJD2D contributed substantially to the full induction of L. monocytogenes -induced IL-12b expression and inflammatory responses in macrophages. These findings identify JMJD2D as an epigenetic regulator of macrophage IL-12b expression and IL-12p70 production, and support its involvement in coordinated macrophage and CD8 + T cell responses during L. monocytogenes infection. Our findings further suggest that the JMJD2D-IL-12b/IL-12p70-IFNγ regulatory axis contributes to host antimicrobial immunity and provide a basis for further investigation of JMJD2D as a potential modulator of antibacterial immune responses.