IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8
Sánchez Fernández, Alba (Universitat Autònoma de Barcelona. Institut de Neurociències)
Zandee, Stephanie (Université de Montréal. Department of Neuroscience)
Amo Aparicio, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)
Charabati, Marc (Université de Montréal. Department of Neuroscience)
Prat, Alexandre (Université de Montréal. Department of Neuroscience)
Garlanda, Cecilia (Humanitas Clinical and Research Center)
Eisenmesser, Elan Z. (University of Colorado. Department of Biochemistry and Molecular Genetics)
Dinarello, Charles A. (Radboud University Medical Center. Department of Medicine)
López-Vales, Rubèn (Universitat Autònoma de Barcelona. Institut de Neurociències)
Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia

Data:	2021
Resum:	Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.
Ajuts:	Ministerio de Economía y Competitividad SAF2016-79774-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Multiple sclerosis ; Experimental autoimmune encephalomyelitis ; IL-37 ; IL-1R8 ; Cytokines
Publicat a:	Theranostics, Vol. 11 Núm. 1 (january 2021) , p. 1-13, ISSN 1838-7640

DOI: 10.7150/thno.47435
PMID: 33391457

13 p, 1.5 MB

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