AbstractsBiology & Animal Science

Functional roles of the Aryl Hydrocarbon Receptor in Experimental Autoimmune Encephalomyelitis

by Chiara Redaelli




Institution: Universität Heidelberg
Department: The Faculty of Bio Sciences
Degree: PhD
Year: 2015
Record ID: 1114508
Full text PDF: http://www.ub.uni-heidelberg.de/archiv/18555


Abstract

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease, which affects around three million people worldwide and is the main cause of disability in young adults in the US and western Europe. It is characterised by lymphocytic infiltration into the central nervous system (CNS) and destruction of oligodendrocytes, followed by neuronal cell death. The definite cause of the disease is unknown, but most likely consists of an interplay of genetic and environmental factors. Epidemiological studies have demonstrated that the incidence and severity of MS is inversely correlated with exposure to UV light. Recent evidence has raised doubt for the UV-mediated production of vitamin D as the sole responsible factor for the protective effect of UV light. The aryl hydrocarbon receptor (AhR) is a key regulator of immune responses in neuroinflammation and can be activated by UV photoproducts of tryptophan. We therefore investigated the role of UVB-mediated AhR activation in experimental autoimmune encephalomyelitis, the mouse model of MS. Animals lacking the AhR did not get any benefit from UVB irradiation, while the irradiation of specific AhR reporter mice showed an increased bioluminescence signal in the skin, which reflected an AhR activation upon UV treatment. Furthermore, we identified inosine as a potent activator of the AhR accumulating in skin of irradiated mice. Antigen presenting cells homed from the skin to the draining lymph nodes due to UVB irradiation and AhR activation, where they were able to induce regulatory T-cells, the so-called UV-Tregs. In addition to its effects on the immune system, the AhR is widely studied as an important mediator of toxicity for xenobiotics. While we could not prove that the immunosuppressive effect of Teriflunomide, a newly approved drug for MS treatment, could be in part mediated by AhR activation, we identified the AhR as the main mediator of its gastrointestinal toxicity. AhR deficient animals treated with Teriflunomide died due to gastroenteritis, intestinal bleeding and liver toxicity. Our data showed that, in the mouse model of MS, the AhR is a key molecule in mediating the immunosuppressive effect of UVB light and the metabolisation of the MS drug Teriflunomide. Pharmacological targeting of the AhR could enhance the beneficial effects of UVB light. Genetic polymorphisms of the AhR in MS patients could explain the increased side effects of Teriflunomide. Multiple Sklerose (MS) ist eine Autoimmun- und neurodegenerative Erkrankung, von der circa drei Millionen Menschen weltweit betroffen sind und die Hauptursache von Behinderungen bei jungen Erwachsenen in den USA und Europa ist. MS ist charakterisiert durch lymphatische Infiltrationen ins zentrale Nervensystem (ZNS) und die Zerstörung von Oligodendrozyten, gefolgt von neuronalem Zelltod. Die Ursache dieser Krankheit ist unbekannt, beinhaltet aber höchstwahrscheinlich das Zusammenspiel genetischer und umweltbedingter Faktoren. Epidemiologische Studien haben gezeigt, dass die Inzidenz und Schwere der MS…