OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

SignificanceAlthough a high-serum osteoprotegerin (OPG) level is associated with an unfavorable outcome in ischemic stroke, it is unclear whether OPG is a culprit or an innocent bystander. Here we show that the deletion of OPG and enhanced RANKL/RANK signaling contribute to the reduction of infarct volume with lower brain edema, whereas infarct volume is increased by reduced RANKL/RANK signaling inOPG−/−mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in ischemic brain and were expressed in activated microglia and macrophages. Enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture. Our findings propose anti-inflammatory roles for RANKL/RANK signaling in ischemic brains.