title: G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration.
abstract: OBJECTIVE
  The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.
  
  
  METHODS
  We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1β-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation.
  
  
  RESULTS
  We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.
  
  
  CONCLUSIONS
  Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.
authors.affiliation: Inserm, U676, Hôpital Robert Debré, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Stéphane
authors.initials: S
authors.lastname: Peineau
authors.forename: Cora
authors.initials: C
authors.lastname: Nijboer
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kaindl
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sigaut
authors.forename: Géraldine
authors.initials: G
authors.lastname: Favrais
authors.forename: Frank
authors.initials: F
authors.lastname: Plaisant
authors.forename: Natacha
authors.initials: N
authors.lastname: Teissier
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouadon
authors.forename: Alain
authors.initials: A
authors.lastname: Lombet
authors.forename: Elie
authors.initials: E
authors.lastname: Saliba
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Cobi
authors.initials: C
authors.lastname: Heijnen
authors.forename: Jean
authors.initials: J
authors.lastname: Mantz
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007051:Ibotenic Acid / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D053583:Interleukin-1beta / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D054799:Phospholipase C beta / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D007051:Ibotenic Acid; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; C517657:CAMK2A protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054799:Phospholipase C beta; D002118:Calcium