Trained immunity in pristane induced lupus 2213

Abstract Description Trained immunity is a functional state of the innate immune system that is characterized by long-term epigenetic and metabolic reprogramming of cells associated with potent immune responses. It benefits to host defense but has also detrimental outcomes in immune-mediated and chronic inflammatory diseases. Pristane treated mice develop clinical and serological manifestations of lupus along with a TLR7-driven type I interferon signature. Although trained immunity is seen in many cell types, we will focus on monocytes/M?, which are central to the induction of lupus by pristane. Akt-mTOR-Hif1α-mediated reprogramming of metabolism toward aerobic glycolysis is critical to the enhanced innate immune response in trained immunity. Epigenetic reprogramming in trained immunity is associated with trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter regions of proinflammatory genes like Tnfa. We found the monocyte and macrophages from pristane treated mice showed increased glycolytic metabolism, HIF1a expression and TNFa production. In vitro, exposure of mouse J774 or RAW264.7 to pristane substantially increases R848 and LPS, but not CpG, stimulated IL-6, CCL2, and TNFα production. The augmented responsiveness to TLR7 or TLR4 ligand stimulation is not seen after MO or squalene exposure and is not due to increased intracellular (or cell surface) TLR7 expression. These findings indicate the role of trained innate immunity in the mechanism of pristane induced lupus. Funding Sources NIAMS R01-AR44731 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)