Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway

Guangrui Li; Ryo Yamasaki; Mei Fang; Katsuhisa Masaki; Hirofumi Ochi; Takuya Matsushita; Jun-Ichi Kira

doi:10.1038/s41598-018-20390-5

Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway

Sci Rep. 2018 Jan 31;8(1):1933. doi: 10.1038/s41598-018-20390-5.

Authors

Guangrui Li¹, Ryo Yamasaki², Mei Fang¹, Katsuhisa Masaki¹, Hirofumi Ochi³, Takuya Matsushita¹, Jun-Ichi Kira⁴

Affiliations

¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
² Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. [email protected].
³ Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Matsuyama, 791-0295, Japan.
⁴ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. [email protected].

Abstract

We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3⁺ T, F4/80⁺, and CD169⁺ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

Publication types

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

MeSH terms

Animals
Antirheumatic Agents / administration & dosage
Antirheumatic Agents / pharmacology
Antirheumatic Agents / therapeutic use*
Chromones / administration & dosage
Chromones / pharmacology
Chromones / therapeutic use*
Chronic Disease
Cyclooxygenase 2 / metabolism
Down-Regulation* / drug effects
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Female
Immunization
Inflammation / pathology
Leukocytes / pathology
Lipopolysaccharides
Lymphocyte Activation / drug effects
Macrophage Activation / drug effects
Macrophages / drug effects
Macrophages / metabolism*
Macrophages / pathology
Mice, Inbred C57BL
Microglia / drug effects
Microglia / metabolism*
Microglia / pathology
Myelin-Oligodendrocyte Glycoprotein
NF-kappa B / metabolism*
Peptide Fragments
Phenotype
Signal Transduction*
Spinal Cord / metabolism
Spinal Cord / pathology
Spleen / drug effects
Spleen / pathology
Sulfonamides / administration & dosage
Sulfonamides / pharmacology
Sulfonamides / therapeutic use*
Th1 Cells / drug effects
Th1 Cells / immunology
Th17 Cells / drug effects
Th17 Cells / immunology
Up-Regulation / drug effects

Substances

Antirheumatic Agents
Chromones
Lipopolysaccharides
Myelin-Oligodendrocyte Glycoprotein
NF-kappa B
Peptide Fragments
Sulfonamides
myelin oligodendrocyte glycoprotein (35-55)
iguratimod
Cyclooxygenase 2