title: Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain.
abstract: Neuropathic pain from injury to the peripheral and CNS represents a major health care issue. We have investigated the role of IL-33/IL-33 receptor (ST2) signaling in experimental models of neuropathic pain in mice. Chronic constriction injury (CCI) of the sciatic nerve induced IL-33 production in the spinal cord. IL-33/citrine reporter mice revealed that oligodendrocytes are the main cells expressing IL-33 within the spinal cord together with a minor expression by neurons, microglia. and astrocytes. CCI-induced mechanical hyperalgesia was reduced in IL-33R (ST2)(-/ -) mice compared with wild-type (WT) mice. Intrathecal treatment of WT mice with soluble IL-33 receptor (IL-33 decoy receptor) markedly reduced CCI-induced hyperalgesia. Consistent with these observations, intrathecal injection of IL-33 enhanced CCI hyperalgesia and induced hyperalgesia in naive mice. IL-33-mediated hyperalgesia during CCI was dependent on a reciprocal relationship with TNF-α and IL-1β. IL-33-induced hyperalgesia was markedly attenuated by inhibitors of PI3K, mammalian target of rapamycin, MAPKs (p38, ERK, and JNK), NF-κB, and also by the inhibitors of glial cells (microglia and astrocytes). Furthermore, targeting these signaling pathways and cells inhibited IL-33-induced TNF-α and IL-1β production in the spinal cord. Our study, therefore, reveals an important role of oligodendrocyte-derived IL-33 in neuropathic pain.
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Ana C
authors: AC
authors: Zarpelon
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Francielle C
authors: FC
authors: Rodrigues
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Alexandre H
authors: AH
authors: Lopes
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Guilherme R
authors: GR
authors: Souza
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Thacyana T
authors: TT
authors: Carvalho
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Larissa G
authors: LG
authors: Pinto
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Damo
authors: D
authors: Xu
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Sergio H
authors: SH
authors: Ferreira
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Jose C
authors: JC
authors: Alves-Filho
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Iain B
authors: IB
authors: McInnes
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Bernhard
authors: B
authors: Ryffel
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Valérie F J
authors: VF
authors: Quesniaux
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Flora
authors: F
authors: Reverchon
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Stéphane
authors: S
authors: Mortaud
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Arnaud
authors: A
authors: Menuet
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Foo Y
authors: FY
authors: Liew
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Fernando Q
authors: FQ
authors: Cunha
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: Thiago M
authors: TM
authors: Cunha
authors: *Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; Unités Mixtes de Recherche 7355, Centre National de la Recherche Scientifique Experimental and Molecular Immunology and Neurogenetics, Orléans, France; Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France; and School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China waldiceujr@yahoo.com.br.
authors: Waldiceu A
authors: WA
authors: Verri
mesh_terms: D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism*; D000067596:Interleukin-33 / Q000378:metabolism*; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D017288:Pain Threshold / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000067531:Alarmins; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D019869:Phosphatidylinositol 3-Kinases
keywords: MAPK; NF-κB; glial cells; hyperalgesia; mTOR