Journal Article

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

Morishita, Ryuichi, Wakayama, Kouji, Kurinami, Hitomi, Tenma, Akiko, Zhengda, Pang, Shimamura, Munehisa, Koriyama, Hiroshi, Tomioka, Hideki, Nakagami, Hironori, Osako, Mariana K.

2014

Overview

Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG ⁻/⁻ mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG ⁻/⁻ mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl ₂, or H ₂O ₂-stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biological Sciences / Body temperature / Brain / Brain - immunology / Brain - metabolism / Brain - pathology / Brain edema / Brain Edema - immunology / Brain Edema - metabolism / Brain Edema - pathology / Brain Ischemia - immunology / Brain Ischemia - metabolism / Brain Ischemia - pathology / Cell Death - drug effects / Cell Death - immunology / Cells, Cultured / clinical trials / Coculture Techniques / Cytokines / Cytokines - immunology / Cytokines - metabolism / Edema / Encephalitis - immunology / Encephalitis - metabolism / Encephalitis - pathology / glutamic acid / Hydrogen peroxide / infarction / Inflammation / Ischemia / Lipopolysaccharides - pharmacology / macrophages / Macrophages - immunology / Macrophages - metabolism / Messenger RNA / Mice / Mice, Inbred C57BL / Mice, Knockout / Microglia / Microglia - immunology / Microglia - metabolism / mixed culture / neuroglia / Neurons / Neurons - immunology / Neurons - metabolism / neuroprotective effect / neutralizing antibodies / Osteoprotegerin - genetics / Osteoprotegerin - immunology / Osteoprotegerin - metabolism / Proteins / RANK Ligand - genetics / RANK Ligand - immunology / RANK Ligand - metabolism / Receptor Activator of Nuclear Factor-kappa B - genetics / Receptor Activator of Nuclear Factor-kappa B - immunology / Receptor Activator of Nuclear Factor-kappa B - metabolism / Receptors / RNA, Messenger - metabolism / Rodents / signal transduction / Signal Transduction - immunology / Stroke / Strokes / Toll-like receptors / transcription factor NF-kappa B