PMID- 26025257 OWN - NLM STAT- MEDLINE DCOM- 20160808 LR - 20231213 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 12 DP - 2015 May 30 TI - Neuronal self-injury mediated by IL-1beta and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia. PG - 111 LID - 10.1186/s12974-015-0330-8 [doi] LID - 111 AB - 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-1beta 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-1beta 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-1beta was first detected in infarcted neocortical and striatal areas and later in glial cells of the adjacent white matter. Neuronal IL-1beta 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-1beta mRNA and MMP-9 neuronal synthesis. Immediately post-HI, neuronal IL-1beta 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-1beta blockade prevented PMN infiltration and oriented the phenotype of macrophagic/microglial cells towards anti-inflammatory and neurotrophic M2 profile. IL-1beta 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-1beta and MMP-9. In addition, it reinforced the translational neuroprotective potential of IL-1 blockers to alleviate human perinatal brain injuries. FAU - Savard, Alexandre AU - Savard A AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Alexandre.Savard@usherbrooke.ca. FAU - Brochu, Marie-Elsa AU - Brochu ME AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Marie-Elsa.Brochu@usherbrooke.ca. FAU - Chevin, Mathilde AU - Chevin M AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Mathilde.Chevin@usherbrooke.ca. FAU - Guiraut, Clemence AU - Guiraut C AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Clemence.Guiraut@usherbrooke.ca. FAU - Grbic, Djordje AU - Grbic D AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Djordje.Grbic@usherbrooke.ca. FAU - Sebire, Guillaume AU - Sebire G AD - Laboratoire de Neurologie Pediatrique, Universite de Sherbrooke, Sherbrooke, QC, Canada. Guillaume.Sebire@Usherbrooke.ca. AD - McGill University, 2300 Tupper street, H3H 1P3, Montreal, QC, Canada. Guillaume.Sebire@Usherbrooke.ca. LA - eng GR - Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150530 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Interleukin 1 Receptor Antagonist Protein) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ripk3 protein, rat) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Age Factors MH - Animals MH - Animals, Newborn MH - *Brain Diseases/etiology/metabolism/pathology MH - Caspase 3/metabolism MH - Cerebral Palsy/chemically induced/*complications/immunology MH - Disease Models, Animal MH - Glial Fibrillary Acidic Protein/metabolism MH - Hypoxia-Ischemia, Brain/*complications/pathology MH - Interleukin 1 Receptor Antagonist Protein/genetics/metabolism MH - Interleukin-1beta/genetics/*metabolism MH - Lipopolysaccharides/toxicity MH - Matrix Metalloproteinase 9/genetics/*metabolism MH - Motor Activity/drug effects MH - Neurons/*metabolism/pathology MH - Rats MH - Rats, Inbred Lew MH - Receptor-Interacting Protein Serine-Threonine Kinases/metabolism MH - Stereotyped Behavior/drug effects PMC - PMC4449972 EDAT- 2015/05/31 06:00 MHDA- 2016/08/09 06:00 PMCR- 2015/05/30 CRDT- 2015/05/31 06:00 PHST- 2014/12/04 00:00 [received] PHST- 2015/05/20 00:00 [accepted] PHST- 2015/05/31 06:00 [entrez] PHST- 2015/05/31 06:00 [pubmed] PHST- 2016/08/09 06:00 [medline] PHST- 2015/05/30 00:00 [pmc-release] AID - 10.1186/s12974-015-0330-8 [pii] AID - 330 [pii] AID - 10.1186/s12974-015-0330-8 [doi] PST - epublish SO - J Neuroinflammation. 2015 May 30;12:111. doi: 10.1186/s12974-015-0330-8.