Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences

Paolo Fagone; Emanuela Mazzon; Eugenio Cavalli; Alessia Bramanti; Maria Cristina Petralia; Katia Mangano; Yousef Al-Abed; Placido Bramati; Ferdinando Nicoletti

doi:10.1016/j.jneuroim.2018.06.009

Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences

J Neuroimmunol. 2018 Sep 15:322:46-56. doi: 10.1016/j.jneuroim.2018.06.009. Epub 2018 Jun 15.

Authors

Paolo Fagone¹, Emanuela Mazzon², Eugenio Cavalli¹, Alessia Bramanti², Maria Cristina Petralia³, Katia Mangano¹, Yousef Al-Abed⁴, Placido Bramati², Ferdinando Nicoletti⁵

Affiliations

¹ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
² IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
³ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Department of Formative Processes, University of Catania, Catania, Italy.
⁴ Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, New York, United States.
⁵ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy. Electronic address: [email protected].

PMID: 29935880
DOI: 10.1016/j.jneuroim.2018.06.009

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions involved in the pathogenesis of autoimmune disorders, including Multiple Sclerosis (MS). We have first evaluated in silico the involvement of MIF, its homologue D-DT, and the receptors CD74, CD44, CXCR2 and CXCR4 in encephalitogenic T cells from a mouse model of MS, the Experimental Allergic Encephalomyelitis (EAE), as well as in circulating T helper cells from MS patients. We show an upregulation of the receptors involved in MIF signaling both in the animal model and in patients. Also, a significant increase in MIF receptors is found in the CNS lesions associated to MS. Finally, the specific inhibitor of MIF, ISO-1, improved both ex vivo and in vivo the features of EAE. Overall, our data indicate that there is a significant involvement of the MIF pathway in MS ethiopathogenesis and that interventions specifically blocking MIF receptors may represent useful therapeutic approaches in the clinical setting.

Keywords: CD74; DDT; EAE; Macrophage migration inhibitory factor; Multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Differentiation, B-Lymphocyte / biosynthesis
Antigens, Differentiation, B-Lymphocyte / genetics
Antigens, Differentiation, B-Lymphocyte / physiology
Autoantigens / immunology
Cells, Cultured
Central Nervous System / metabolism
Central Nervous System / pathology
Computer Simulation
Encephalomyelitis, Autoimmune, Experimental / etiology*
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Female
Gene Expression Regulation / immunology
Histocompatibility Antigens Class II / biosynthesis
Histocompatibility Antigens Class II / genetics
Histocompatibility Antigens Class II / physiology
Humans
Hyaluronan Receptors / biosynthesis
Hyaluronan Receptors / genetics
Hyaluronan Receptors / physiology
Intramolecular Oxidoreductases / antagonists & inhibitors
Intramolecular Oxidoreductases / biosynthesis
Intramolecular Oxidoreductases / genetics
Intramolecular Oxidoreductases / physiology*
Isoxazoles / pharmacology
Macrophage Migration-Inhibitory Factors / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Immunological
Multiple Sclerosis / etiology*
Multiple Sclerosis / immunology
Multiple Sclerosis / metabolism
Myelin-Oligodendrocyte Glycoprotein / immunology
Oligodendroglia / metabolism
Oligodendroglia / pathology
Peptide Fragments / immunology
RNA, Messenger / biosynthesis
Receptors, CXCR4 / biosynthesis
Receptors, CXCR4 / genetics
Receptors, CXCR4 / physiology
Receptors, Interleukin-8B / biosynthesis
Receptors, Interleukin-8B / genetics
Receptors, Interleukin-8B / physiology
Signal Transduction
T-Lymphocytes, Helper-Inducer / immunology

Substances

3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester
Antigens, Differentiation, B-Lymphocyte
Autoantigens
CD44 protein, human
CXCR2 protein, human
CXCR4 protein, human
CXCR4 protein, mouse
Cd44 protein, mouse
Histocompatibility Antigens Class II
Hyaluronan Receptors
Isoxazoles
Macrophage Migration-Inhibitory Factors
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
RNA, Messenger
Receptors, CXCR4
Receptors, Interleukin-8B
invariant chain
myelin oligodendrocyte glycoprotein (35-55)
Intramolecular Oxidoreductases
MIF protein, human
Mif protein, mouse
dopachrome isomerase