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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

Overview of attention for article published in Journal of Neuroinflammation, May 2015
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3 tweeters

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30 Dimensions

Readers on

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37 Mendeley
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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
Published in
Journal of Neuroinflammation, May 2015
DOI 10.1186/s12974-015-0330-8
Pubmed ID
Authors

Alexandre Savard, Marie-Elsa Brochu, Mathilde Chevin, Clémence Guiraut, Djordje Grbic, Guillaume Sébire

Abstract

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. 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. 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. 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.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 37 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 37 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 7 19%
Student > Doctoral Student 6 16%
Student > Ph. D. Student 6 16%
Student > Bachelor 4 11%
Researcher 3 8%
Other 5 14%
Unknown 6 16%
Readers by discipline Count As %
Psychology 8 22%
Neuroscience 7 19%
Medicine and Dentistry 6 16%
Agricultural and Biological Sciences 4 11%
Pharmacology, Toxicology and Pharmaceutical Science 3 8%
Other 3 8%
Unknown 6 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 June 2015.
All research outputs
#2,529,839
of 5,208,706 outputs
Outputs from Journal of Neuroinflammation
#369
of 802 outputs
Outputs of similar age
#88,855
of 174,785 outputs
Outputs of similar age from Journal of Neuroinflammation
#31
of 52 outputs
Altmetric has tracked 5,208,706 research outputs across all sources so far. This one has received more attention than most of these and is in the 50th percentile.
So far Altmetric has tracked 802 research outputs from this source. They receive a mean Attention Score of 3.7. This one has gotten more attention than average, scoring higher than 53% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 174,785 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 52 others from the same source and published within six weeks on either side of this one. This one is in the 40th percentile – i.e., 40% of its contemporaries scored the same or lower than it.