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NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients
Journal article

NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients

  • Malhotra, Sunny Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Costa, Carme Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Eixarch, Herena Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Keller, Christian W ORCID Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland
  • Amman, Lukas Faculty of Biology, University of Freiburg, Freiburg, Germany
  • Martínez-Banaclocha, Helios Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
  • Midaglia, Luciana Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Sarró, Eduard Renal Physiopathology Group, Institut de Recerca Vall d’Hebron (VHIR) - CIBBIM Nanomedicine, Barcelona, Spain
  • Machín-Díaz, Isabel Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
  • Villar, Luisa M ORCID Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), Madrid, Spain
  • Triviño, Juan Carlos Genomic Systems, Valencia, Spain
  • Oliver-Martos, Begoña Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain
  • Parladé, Laura Navarro Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Calvo-Barreiro, Laura Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Matesanz, Fuencisla Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
  • Vandenbroeck, Koen IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  • Urcelay, Elena Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
  • Martínez-Ginés, María-Luisa Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  • Tejeda-Velarde, Amalia Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), Madrid, Spain
  • Fissolo, Nicolás Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Castilló, Joaquín Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Sanchez, Alex Statistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca, Barcelona, Spain
  • Robertson, Avril A B School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
  • Clemente, Diego Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
  • Prinz, Marco Center for NeuroModulation (NeuroModul), Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Pelegrin, Pablo Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
  • Lünemann, Jan D Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland
  • Espejo, Carmen Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  • Montalban, Xavier Center for Multiple Sclerosis, St, Michael’s Hospital, University of Toronto, Toronto, ON, Canada
  • Comabella, Manuel Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • 2020-4-13
Published in:
  • Brain. - Oxford University Press (OUP). - 2020, vol. 143, no. 5, p. 1414-1430
Clinical Neurology
English Abstract
Primary progressive multiple sclerosis is a poorly understood disease entity with no specific prognostic biomarkers and scarce therapeutic options. We aimed to identify disease activity biomarkers in multiple sclerosis by performing an RNA sequencing approach in peripheral blood mononuclear cells from a discovery cohort of 44 untreated patients with multiple sclerosis belonging to different clinical forms and activity phases of the disease, and 12 healthy control subjects. A validation cohort of 58 patients with multiple sclerosis and 26 healthy control subjects was included in the study to replicate the RNA sequencing findings. The RNA sequencing revealed an interleukin 1 beta (IL1B) signature in patients with primary progressive multiple sclerosis. Subsequent immunophenotyping pointed to blood monocytes as responsible for the IL1B signature observed in this group of patients. Functional experiments at baseline measuring apoptosis-associated speck-like protein containing a CARD (ASC) speck formation showed that the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome was overactive in monocytes from patients with primary progressive multiple sclerosis, and canonical NLRP3 inflammasome activation with a combination of ATP plus lipopolysaccharide was associated with increased IL1B production in this group of patients. Primary progressive multiple sclerosis patients with high IL1B gene expression levels in peripheral blood mononuclear cells progressed significantly faster compared to patients with low IL1B levels based on the time to reach an EDSS of 6.0 and the Multiple Sclerosis Severity Score. In agreement with peripheral blood findings, both NLRP3 and IL1B expression in brain tissue from patients with primary progressive multiple sclerosis was mainly restricted to cells of myeloid lineage. Treatment of mice with a specific NLRP3 inflammasome inhibitor attenuated established experimental autoimmune encephalomyelitis disease severity and improved CNS histopathology. NLRP3 inflammasome-specific inhibition was also effective in reducing axonal damage in a model of lipopolysaccharide-neuroinflammation using organotypic cerebellar cultures. Altogether, these results point to a role of IL1B and the NLRP3 inflammasome as prognostic biomarker and potential therapeutic target, respectively, in patients with primary progressive multiple sclerosis.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.ch/global/documents/203891
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