Dendritic cell iron overload exacerbates acetaminophen hepatotoxicity

Liver immune homeostasis relies on the coordinated actions of various immune cells including dendritic cells (DCs), which exert regulatory roles in both innate and adaptive immunity. Various pieces of evidence demonstrate that the properties of immune cells are highly influenced by iron metabolism. However, the roles of iron metabolism on DC function remain poorly understood. Here, we show that mice with iron overload in DCs displayed worsening of liver injury and mortality in acetaminophen (APAP) -induced acute hepatitis. Enhanced neutrophil infiltration was observed in these mice during the progression of liver injury. DCs with iron overload showed increased expression of the neutrophil-attracting cytokine IL-6, thereby accelerating liver injury. Mechanistic studies revealed that iron enhanced the recruitment of NF-κB to the IL-6 promoter upon TLR4 activation. Our findings provide an insight into the regulatory mechanisms by which iron metabolism influences DC function. This study also highlights the critical role of the DC-IL-6-neutrophil axis in acute liver injury.