Prostaglandin E2-EP2-NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms.
Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor κB (NF-κB), and inflammatory signaling involving prostaglandin E2(PGE2) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-κB activation during intracranial aneurysm development in mice showed that NF-κB was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an IκBα mutant that restricts NF-κB activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-κB activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-α (TNF-α) to activate NF-κB and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.
Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.|Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Tomohiro
T
Aoki
Neurosurgery Research Group, Biomedicum Helsinki, Helsinki 00029 HUS, Finland.|Hemorrhagic Brain Pathology Research Group, NeuroCenter, Kuopio University Hospital, Kuopio 70029 KYS, Finland.|Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio 70029 KYS, Finland.
Juhana
J
Frȍsen
Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Miyuki
M
Fukuda
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan.|Genetic Engineering Team, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan.
Kana
K
Bando
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan.
Go
G
Shioi
Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
Keiichi
K
Tsuji
Neurosurgery Research Group, Biomedicum Helsinki, Helsinki 00029 HUS, Finland.
Eliisa
E
Ollikainen
Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
Kazuhiko
K
Nozaki
Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio 70211, Finland.
Johanna
J
Laakkonen
Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. snaru@mfour.med.kyoto-u.ac.jp.|Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Shuh
S
Narumiya
D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D002532:Intracranial Aneurysm / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001384:Azetidines; D018932:Chemokine CCL2; D016328:NF-kappa B; D058307:Receptors, Prostaglandin E, EP2 Subtype; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; C570688:1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid; D015232:Dinoprostone