OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice.
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, CoCl2, or H2O2-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.
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Munehisa
M
Shimamura
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Hironori
H
Nakagami
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Mariana K
MK
Osako
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Hitomi
H
Kurinami
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Hiroshi
H
Koriyama
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Japan;
Pang
P
Zhengda
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and.
Hideki
H
Tomioka
Division of Vascular Medicine and Epigenetics, Osaka University United Graduate School of Child Development, Osaka 565-0871, Japan;
Akiko
A
Tenma
Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Kouji
K
Wakayama
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and morishit@cgt.med.osaka-u.ac.jp.
Ryuichi
R
Morishita
D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D016207:Cytokines; D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse
cerebral ischemia; immune cells; neuroprotection