title: EP2 Receptor Signaling Regulates Microglia Death.
abstract: The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We show here that activation of the E prostanoid receptor 2 (EP2, PTGER2) for prostaglandin E2 mediates microglial death induced by LPS/IL-13, and that EP2 activation by agonist alone kills microglia. Both EP2 antagonists and reactive oxygen scavengers block microglial death induced by either LPS/IL-13 or EP2 activation. By contrast, the homeostatic induction of heme oxygenase 1 (Hmox1) by LPS/IL-13 or EP2 activation protects microglia. Both the Hmox1 inducer cobalt protoporphyrin and a compound that releases the Hmox1 product carbon monoxide (CO) attenuated microglial death produced by LPS/IL-13. Whereas CO reduced COX-2 protein expression, EP2 activation increased Hmox1 and COX-2 expression at both the mRNA and protein level. Interestingly, caspase-1 inhibition prevented microglial death induced by either LPS/IL-13 or low (but not high) concentrations of butaprost, suggestive of a predominantly pyroptotic mode of death. Butaprost also caused the expression of activated caspase-3 in microglia, pointing to apoptosis. These results indicate that EP2 activation, which initially promotes microglial activation, later causes delayed death of activated microglia, potentially contributing to the resolution phase of neuroinflammation.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.) yujiao.fu@gmail.com.
authors.forename: Yujiao
authors.identifier: http://orcid.org/0000-0002-6168-7067
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).
authors.forename: Myung-Soon
authors.initials: MS
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).
authors.forename: Eunhye
authors.initials: E
authors.lastname: Joe
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (Y.F., M.-S.Y., J.J., T.G., R.D.); Neurology Department, Xiangya Hospital, Hunan, China (Y.F.); and Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea (M.-S.Y., E.J.).
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D018793:Interleukin-13 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D010862:Pilocarpine; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D018793:Interleukin-13; D008070:Lipopolysaccharides; C545645:Ptger2 protein, mouse; C545646:Ptger2 protein, rat; D058307:Receptors, Prostaglandin E, EP2 Subtype; D010862:Pilocarpine; D000527:Alprostadil; C048491:butaprost