The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor

Johannes Berg; Yasaman Mahmoudjanlou; Alexander Duscha; Megan G Massa; Jan Thöne; Charlotte Esser; Ralf Gold; Aiden Haghikia

doi:10.1016/j.jneuroim.2016.06.003

The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor

J Neuroimmunol. 2016 Sep 15:298:9-15. doi: 10.1016/j.jneuroim.2016.06.003. Epub 2016 Jun 9.

Authors

Johannes Berg¹, Yasaman Mahmoudjanlou¹, Alexander Duscha¹, Megan G Massa¹, Jan Thöne¹, Charlotte Esser², Ralf Gold³, Aiden Haghikia⁴

Affiliations

¹ Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
² Leibniz-Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
³ Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany. Electronic address: ralf.gold@rub.de.
⁴ Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany. Electronic address: aiden.haghikia@rub.de.

PMID: 27609269
DOI: 10.1016/j.jneuroim.2016.06.003

Abstract

Though several functional properties of laquinimod have been identified, our understanding of the underlying mechanisms is still incomplete. Since the compound elicits similar immunomodulatory effects to ligands of the aryl hydrocarbon receptor (AhR), we compared the efficacy of laquinimod in experimental autoimmune encephalomyelitis (EAE)-afflicted wild-type and AhR-deficient mice. Laquinimod failed to ameliorate clinical symptoms and leukocyte infiltration in AhR-deficient mice; however, treatment exerted neuroprotection by elevation of brain-derived neurotrophic factor (BDNF) independent of genetic profile. Thus, our data identify the AhR pathway in these mutant mice as crucial for the immunomodulatory, but not neuroprotective, efficacy of laquinimod in EAE.

Keywords: Aryl hydrocarbon receptor; Experimental autoimmune encephalomyelitis; Immunomodulation; Laquinimod.

MeSH terms

Analysis of Variance
Animals
Axons / drug effects
Axons / pathology
Brain-Derived Neurotrophic Factor / genetics
Brain-Derived Neurotrophic Factor / metabolism
CD3 Complex / metabolism
Demyelinating Autoimmune Diseases, CNS / chemically induced
Demyelinating Autoimmune Diseases, CNS / drug therapy*
Demyelinating Autoimmune Diseases, CNS / immunology*
Disease Models, Animal
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Immunologic Factors / therapeutic use*
Leukemic Infiltration / drug therapy
Mice, Inbred C57BL
Mice, Knockout
Myelin-Oligodendrocyte Glycoprotein / toxicity
Peptide Fragments / toxicity
Quinolones / therapeutic use*
RNA, Messenger / metabolism
Rats
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism*
Spinal Cord / pathology
T-Lymphocytes / drug effects
White Matter / drug effects
White Matter / pathology

Substances

Brain-Derived Neurotrophic Factor
CD3 Complex
Immunologic Factors
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
Quinolones
RNA, Messenger
Receptors, Aryl Hydrocarbon
myelin oligodendrocyte glycoprotein (35-55)
laquinimod