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Langerhans cell histiocytosis (LCH) is an inflammatory disease characterized by abnormal dendritic cells (DCs) with hyperactive ERK signaling, called “LCH cells.” Since DCs rely on ERK signaling to produce inflammatory molecules in response to pathogenic cues, we hypothesized that hyperactive ERK enhances DCs inflammatory responses. We specifically investigated TLR4-induced TNFα production in LCH cells by utilizing the BRAF-V600E^fl/+:CD11c-Cre mouse model of LCH, which hyperactivates ERK in DCs. We measured LPS-induced TNFα production both in vivo and in vitro using splenic CD11c+ cells and bone marrow-derived DCs with or without pharmacologic BRAF^V600E inhibition. We observed a reversible increase in secreted TNFα and a partially reversible increase in TNFα protein per cell, despite a decrease in TLR4 signaling and Tnfa transcripts compared with controls. We examined …