title: NLRP3 inflammasome is associated with the response to IFN-β in patients with multiple sclerosis.
abstract: Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing-remitting multiple sclerosis.
authors.affiliation: 1 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.
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: 1 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Río
authors.affiliation: 2 Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.affiliation: 1 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.
authors.forename: Ramil
authors.initials: R
authors.lastname: Nurtdinov
authors.affiliation: 1 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.
authors.forename: Marta F
authors.initials: MF
authors.lastname: Bustamante
authors.affiliation: 3 Unidad de Gestión Clínica de Neurociencias. Instituto de Biomedicina de Málaga (IBIMA), Hospital Universitario Regional de Málaga, Universidad de Málaga, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.affiliation: 3 Unidad de Gestión Clínica de Neurociencias. Instituto de Biomedicina de Málaga (IBIMA), Hospital Universitario Regional de Málaga, Universidad de Málaga, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Oliver
authors.affiliation: 4 University of Rostock, Department of Neurology, Rostock, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Zettl
authors.affiliation: 5 Pole des Neurosciences et INSERM U1043, Université de Toulouse III, Hopital Purpan, Toulouse, France.
authors.forename: David
authors.initials: D
authors.lastname: Brassat
authors.affiliation: 6 VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.affiliation: 7 Department of Neurology, John Hunter Hospital, Newcastle, Australia, Hunter Medical Research Institute, University of Newcastle, Australia.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: 8 Clinic of Neurology, Clinical Centre of Serbia (CCS), Faculty of Medicine, University of Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Drulovic
authors.affiliation: 9 Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.affiliation: 10 Laboratory of Genetics of Neurological Complex Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.affiliation: 11 Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: García-Merino
authors.affiliation: 1 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: 1 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 manuel.comabella@vhir.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004185:Disability Evaluation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D007155:Immunologic Factors; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D016899:Interferon-beta
keywords: association study; biomarkers; imaging; multiple sclerosis