title: The Chemokine CCL2 Mediates the Seizure-enhancing Effects of Systemic Inflammation.
abstract: Epilepsy is a chronic disorder characterized by spontaneous recurrent seizures. Brain inflammation is increasingly recognized as a critical factor for seizure precipitation, but the molecular mediators of such proconvulsant effects are only partly understood. The chemokine CCL2 is one of the most elevated inflammatory mediators in patients with pharmacoresistent epilepsy, but its contribution to seizure generation remains unexplored. Here, we show, for the first time, a crucial role for CCL2 and its receptor CCR2 in seizure control. We imposed a systemic inflammatory challenge via lipopolysaccharide (LPS) administration in mice with mesial temporal lobe epilepsy. We found that LPS dramatically increased seizure frequency and upregulated the expression of many inflammatory proteins, including CCL2. To test the proconvulsant role of CCL2, we administered systemically either a CCL2 transcription inhibitor (bindarit) or a selective antagonist of the CCR2 receptor (RS102895). We found that interference with CCL2 signaling potently suppressed LPS-induced seizures. Intracerebral administration of anti-CCL2 antibodies also abrogated LPS-mediated seizure enhancement in chronically epileptic animals. Our results reveal that CCL2 is a key mediator in the molecular pathways that link peripheral inflammation with neuronal hyperexcitability.
  
  
  CONCLUSIONS
  Substantial evidence points to a role for inflammation in epilepsy, but currently there is little insight as to how inflammatory pathways impact on seizure generation. Here, we examine the molecular mediators linking peripheral inflammation with seizure susceptibility in mice with mesial temporal lobe epilepsy. We show that a systemic inflammatory challenge via lipopolysaccharide administration potently enhances seizure frequency and upregulates the expression of the chemokine CCL2. Remarkably, selective pharmacological interference with CCL2 or its receptor CCR2 suppresses lipopolysaccharide-induced seizure enhancement. Thus, CCL2/CCR2 signaling plays a key role in linking systemic inflammation with seizure susceptibility.
authors.affiliation: Neuroscience Institute, National Research Council, 56124 Pisa, Italy, Accademia Nazionale dei Lincei, 00165 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cerri
authors.affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Sacha
authors.initials: S
authors.lastname: Genovesi
authors.affiliation: Neuroscience Institute, National Research Council, 56124 Pisa, Italy, Accademia Nazionale dei Lincei, 00165 Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Allegra
authors.affiliation: Neuroscience Institute, National Research Council, 56124 Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pistillo
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom, and.
authors.forename: Ursula
authors.initials: U
authors.lastname: Püntener
authors.affiliation: Angelini SpA, S. Palomba-Pomezia, 00040 Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom, and.
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.affiliation: Neuroscience Institute, National Research Council, 56124 Pisa, Italy, Laboratory of Molecular Neuropathology, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy, caleo@in.cnr.it yuri.bozzi@unitn.it.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bozzi
authors.affiliation: Neuroscience Institute, National Research Council, 56124 Pisa, Italy, caleo@in.cnr.it yuri.bozzi@unitn.it.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0002-4333-6378
authors.initials: M
authors.lastname: Caleo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000150:complications* / Q000473:pathology / Q000517:prevention & control; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology*; D007608:Kainic Acid / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000906:Antibodies; D048588:Benzoxazines; D018932:Chemokine CCL2; D018690:Excitatory Amino Acid Agonists; D007191:Indazoles; D008070:Lipopolysaccharides; D010880:Piperidines; D011422:Propionates; D012333:RNA, Messenger; C573791:RS 102895; D054390:Receptors, CCR2; C079489:bindarit; D007608:Kainic Acid
keywords: CCL2; EEG; seizures; systemic inflammation; temporal lobe epilepsy