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

Abstract

Introduction 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. Methods 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). Results 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. Discussion 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.