title: Neuronal self-injury mediated by IL-1β and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia.
abstract: BACKGROUND
  Inflammation due to remote pathogen exposure combined to hypoxia/ischemia (HI) is one of the most common causes of neonatal encephalopathy affecting at-term or near-term human newborn, which will consequently develop cerebral palsy. Within term-equivalent rat brains exposed to systemic lipopolysaccharide (LPS) plus HI, it was previously showed that neurons produce IL-1β earlier than do glial cells, and that blocking IL-1 was neuroprotective. To further define the mechanisms whereby IL-1 exerts its neurotoxic effect, we hypothesize that IL-1β plays a pivotal role in a direct and/or indirect mechanistic loop of neuronal self-injury through matrix metalloproteinase (MMP)-9.
  
  
  METHODS
  An established preclinical rat model of LPS+HI-induced neonatal encephalopathy was used. In situ hybridization, ELISA, and immunolabeling techniques were employed. Selective blocking compounds allowed addressing the respective roles of IL-1 and MMP-9.
  
  
  RESULTS
  In LPS+HI-exposed forebrains, neuronal IL-1β was first detected in infarcted neocortical and striatal areas and later in glial cells of the adjacent white matter. Neuronal IL-1β played a key role: (i) in the early post-HI exacerbation of neuroinflammation and (ii) in generating both core and penumbral infarcted cerebral areas. Systemically administered IL-1 receptor antagonist (IL-1Ra) reached the brain and bound to the neocortical and deep gray neuronal membranes. Then, IL-1Ra down-regulated IL-1β mRNA and MMP-9 neuronal synthesis. Immediately post-HI, neuronal IL-1β up-regulated cytokine-induced neutrophil chemoattractant (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and inducible nitric oxide synthase. MMP-9 would disrupt the blood-brain barrier, which, combined to CINC-1 up-regulation, would play a role in polymorphonuclear cell (PMN) infiltration into the LPS+HI-exposed brain. IL-1β blockade prevented PMN infiltration and oriented the phenotype of macrophagic/microglial cells towards anti-inflammatory and neurotrophic M2 profile. IL-1β increased the expression of activated caspase-3 and of receptor-interacting-protein (RIP)-3 within infarcted forebrain area. Such apoptotic and necroptotic pathway activations were prevented by IL-1Ra, as well as ensuing cerebral palsy-like brain damage and motor impairment.
  
  
  CONCLUSIONS
  This work uncovered a new paradigm of neuronal self-injury orchestrated by neuronal synthesis of IL-1β and MMP-9. In addition, it reinforced the translational neuroprotective potential of IL-1 blockers to alleviate human perinatal brain injuries.
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Alexandre.Savard@usherbrooke.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Savard
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Marie-Elsa.Brochu@usherbrooke.ca.
authors.forename: Marie-Elsa
authors.initials: ME
authors.lastname: Brochu
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Mathilde.Chevin@usherbrooke.ca.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chevin
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Clemence.Guiraut@usherbrooke.ca.
authors.forename: Clémence
authors.initials: C
authors.lastname: Guiraut
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Djordje.Grbic@usherbrooke.ca.
authors.forename: Djordje
authors.initials: D
authors.lastname: Grbic
authors.affiliation: Laboratoire de Neurologie Pédiatrique, Université de Sherbrooke, Sherbrooke, QC, Canada. Guillaume.Sebire@Usherbrooke.ca.|McGill University, 2300 Tupper street, H3H 1P3, Montreal, QC, Canada. Guillaume.Sebire@Usherbrooke.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sébire
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001927:Brain Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002547:Cerebral Palsy / Q000139:chemically induced / Q000150:complications* / Q000276:immunology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9