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Time-dependent dual effect of NLRP3 inflammasome in brain ischemia
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  • Alejandra Palomino-Antolin,
  • Paloma Narros-Fernández,
  • Victor Farré-Alins,
  • Javier Sevilla-Montero,
  • Celine Decouty-Pérez,
  • Ana Lopez-Rodriguez,
  • Nuria Fernandez,
  • Luis Monge,
  • Ana Casas,
  • Maria Calzada,
  • Javier Egea
Alejandra Palomino-Antolin
Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa
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Paloma Narros-Fernández
Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa
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Victor Farré-Alins
Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa
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Javier Sevilla-Montero
Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Spain
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Celine Decouty-Pérez
Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa
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Ana Lopez-Rodriguez
Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa
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Nuria Fernandez
Facultad Medicina, Universidad Autonoma
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Luis Monge
Universidad Autónoma de Madrid
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Ana Casas
Department of Pharmacology & Personalised Medicine, CARIM, Maastricht University
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Maria Calzada
Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Spain
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Javier Egea
Universidad Autonoma de Madrid
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Abstract

Background: 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.

Peer review status:IN REVISION

18 Dec 2020Submitted to British Journal of Pharmacology
20 Dec 2020Submission Checks Completed
20 Dec 2020Assigned to Editor
31 Dec 2020Editorial Decision: Revise Minor
12 Jan 20211st Revision Received
17 Jan 2021Submission Checks Completed
17 Jan 2021Assigned to Editor
02 Feb 2021Reviewer(s) Assigned
20 Apr 2021Review(s) Completed, Editorial Evaluation Pending
03 May 2021Editorial Decision: Revise Minor