Aryl hydrocarbon receptor in the control of innate immune responses during inflammatory autoimmune diseases of the central nervous system

• Applicant: Professor Dr. Veit Rothhammer
• Subject Area: Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258867603

Multiple Sclerosis (MS) is a autoimmune chronic inflammatory disease of the central nervous system (CNS), in which a complex interplay between the innate and adaptive immune system under the influence of environmental factors causes acute and chronic inflammatory lesions in the CNS, which ultimately lead to neurodegeneration and accumulation of neurologic deficits. Environmental factors have been shown to potently influence induction and maintenance of inflammatory processes, but need to interact with defined ligand-specific receptors. Activation of Aryl hydrocarbon receptor (AhR), a intracellular receptor for endogenous as well as environmental ligands, has been shown to dampen responses in the adaptive immune system by downmodulating not only pathogenic T cell responses. However, its role in the innate immune system, which constitutes the first cellular barrier against environmental factors and shapes adaptive immune responses, is largely unknown. In this project, we propose to use novel transgenic mouse strains, which are selectively deficient for AhR in different cellular subtypes of the innate immune system (monocytes, macrophages or microglia) to study the role of AhR activation in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. In in vitro experiments, the interaction of AhR deficient antigen presenting cells and pathogenic T cells will be further validated in the presence or absence of AhR activating ligands. Next, the molecular network and subcellular interaction partners operational upon AhR activation will be investigated in murine monocytes using advanced molecular genetic and proteomic approaches. Finally, we will examine the newly defined mechanisms in monocytes from MS patients and healthy controls to set up a molecular fingerprint of AhR activation in MS. These observations and potential targets will promote a deeper understanding of the interplay between environmental and endogenous factors, innate and adaptive immunity and may form the molecular basis for the development of novel therapeutic strategies for MS.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Francisco Quintana