The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor.
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.
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
Johannes
J
Berg
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
Yasaman
Y
Mahmoudjanlou
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
Alexander
A
Duscha
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
Megan G
MG
Massa
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany.
Jan
J
Thöne
Leibniz-Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
Charlotte
C
Esser
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany. Electronic address: ralf.gold@rub.de.
Ralf
R
Gold
Department of Neurology, Ruhr-Universität Bochum, 44801 Bochum, Germany. Electronic address: aiden.haghikia@rub.de.
Aiden
A
Haghikia
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D020278:Demyelinating Autoimmune Diseases, CNS / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007155:Immunologic Factors / Q000627:therapeutic use*; D017254:Leukemic Infiltration / Q000188:drug therapy; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D015363:Quinolones / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects; D066127:White Matter / Q000187:drug effects / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D017252:CD3 Complex; D007155:Immunologic Factors; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D015363:Quinolones; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C445081:myelin oligodendrocyte glycoprotein (35-55); C476223:laquinimod
Aryl hydrocarbon receptor; Experimental autoimmune encephalomyelitis; Immunomodulation; Laquinimod