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Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

Alejandra Palomino-Antolin, Paloma Narros-Fernández, Víctor Farré-Alins, Javier Sevilla-Montero, Celine Decouty-Pérez, Ana Belen Lopez-Rodriguez, Nuria Fernández, Luis Monge, Ana I. Casas, María José Calzada, Javier Egea
doi: https://doi.org/10.1101/2020.10.08.332007
Alejandra Palomino-Antolin
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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Paloma Narros-Fernández
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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Víctor Farré-Alins
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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Javier Sevilla-Montero
2Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Spain
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Celine Decouty-Pérez
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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Ana Belen Lopez-Rodriguez
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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Nuria Fernández
3Fluorescence Imaging Group, Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, 28029, Spain
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Luis Monge
3Fluorescence Imaging Group, Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, 28029, Spain
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Ana I. Casas
4Department of Pharmacology and Personalised Medicine, MHeNs, Maastricht University, Maastricht, The Netherlands
5Department of Neurology, University Clinics Essen, Essen, Germany
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María José Calzada
2Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Spain
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Javier Egea
1Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain
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  • For correspondence: javier.egea@inv.uam.es
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Abstract

Background and purpose Post-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.

Methods WT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.

Results We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.

Conclusions These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

Competing Interest Statement

The authors have declared no competing interest.

  • Non-standard Abbreviations and Acronyms

    DAMPs
    damage-associated molecular patterns
    PAMPs
    pathogen-associated molecular patterns
    NLRC4
    NACHT, LRR, CARD domain-containing protein 4
    NLRP3
    NACHT, LRR and PYD domains-containing protein 3
    AIM2
    Absent In Melanoma 2
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    Posted October 09, 2020.
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    Time-dependent dual effect of NLRP3 inflammasome in brain ischemia
    Alejandra Palomino-Antolin, Paloma Narros-Fernández, Víctor Farré-Alins, Javier Sevilla-Montero, Celine Decouty-Pérez, Ana Belen Lopez-Rodriguez, Nuria Fernández, Luis Monge, Ana I. Casas, María José Calzada, Javier Egea
    bioRxiv 2020.10.08.332007; doi: https://doi.org/10.1101/2020.10.08.332007
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    Time-dependent dual effect of NLRP3 inflammasome in brain ischemia
    Alejandra Palomino-Antolin, Paloma Narros-Fernández, Víctor Farré-Alins, Javier Sevilla-Montero, Celine Decouty-Pérez, Ana Belen Lopez-Rodriguez, Nuria Fernández, Luis Monge, Ana I. Casas, María José Calzada, Javier Egea
    bioRxiv 2020.10.08.332007; doi: https://doi.org/10.1101/2020.10.08.332007

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