PMID- 28174280 OWN - NLM STAT- MEDLINE DCOM- 20171117 LR - 20190115 IS - 1937-9145 (Electronic) IS - 1945-0877 (Linking) VI - 10 IP - 465 DP - 2017 Feb 7 TI - Prostaglandin E2-EP2-NF-kappaB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. LID - eaah6037 [pii] LID - 10.1126/scisignal.aah6037 [doi] AB - 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 kappaB (NF-kappaB), and inflammatory signaling involving prostaglandin E(2) (PGE(2)) 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-kappaB activation during intracranial aneurysm development in mice showed that NF-kappaB 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 IkappaBalpha mutant that restricts NF-kappaB activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappaB activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappaB 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. CI - Copyright (c) 2017, American Association for the Advancement of Science. FAU - Aoki, Tomohiro AU - Aoki T AD - Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. AD - Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. FAU - Frosen, Juhana AU - Frosen J AD - Neurosurgery Research Group, Biomedicum Helsinki, Helsinki 00029 HUS, Finland. AD - Hemorrhagic Brain Pathology Research Group, NeuroCenter, Kuopio University Hospital, Kuopio 70029 KYS, Finland. AD - Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio 70029 KYS, Finland. FAU - Fukuda, Miyuki AU - Fukuda M AD - Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. FAU - Bando, Kana AU - Bando K AD - Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan. AD - Genetic Engineering Team, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan. FAU - Shioi, Go AU - Shioi G AD - Genetic Engineering Team, RIKEN Center for Life Science Technologies, Hyogo 650-0047, Japan. FAU - Tsuji, Keiichi AU - Tsuji K AD - Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan. FAU - Ollikainen, Eliisa AU - Ollikainen E AD - Neurosurgery Research Group, Biomedicum Helsinki, Helsinki 00029 HUS, Finland. FAU - Nozaki, Kazuhiko AU - Nozaki K AD - Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan. FAU - Laakkonen, Johanna AU - Laakkonen J AD - Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio 70211, Finland. FAU - Narumiya, Shuh AU - Narumiya S AD - 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. AD - Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. LA - eng PT - Journal Article DEP - 20170207 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - 0 (Azetidines) RN - 0 (Chemokine CCL2) RN - 0 (NF-kappa B) RN - 0 (Receptors, Prostaglandin E, EP2 Subtype) RN - 0 (Tumor Necrosis Factor-alpha) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - I7Z38E70VF (1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Animals MH - Azetidines/pharmacology MH - Blotting, Western MH - Chemokine CCL2/genetics/metabolism MH - Cyclooxygenase 2/genetics/metabolism MH - Dinoprostone/*metabolism MH - Gene Expression Profiling/methods MH - HEK293 Cells MH - Humans MH - Intracranial Aneurysm/drug therapy/genetics/*metabolism MH - Macrophages/*metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Microscopy, Confocal MH - NF-KappaB Inhibitor alpha/genetics/metabolism MH - NF-kappa B/genetics/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors/genetics/*metabolism MH - Signal Transduction/drug effects/genetics MH - Tumor Necrosis Factor-alpha/genetics/metabolism EDAT- 2017/02/09 06:00 MHDA- 2017/11/29 06:00 CRDT- 2017/02/09 06:00 PHST- 2017/02/09 06:00 [entrez] PHST- 2017/02/09 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] AID - 10/465/eaah6037 [pii] AID - 10.1126/scisignal.aah6037 [doi] PST - epublish SO - Sci Signal. 2017 Feb 7;10(465):eaah6037. doi: 10.1126/scisignal.aah6037.