P8	Endothelial calcium signals in the control of neuroinflammation and neurodegeneration

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Project 8 addresses the links between calcium signals in endothelial cells, amino acid metabolites, and blood brain barrier (BBB) dysfunction in experimental autoimmune encephalomyelitis and MS.

Based on preparatory calcium imaging experiments performed in collaboration with Fairless/Draguhn (Neurology Heidelberg/Physiology Heidelberg, project 3) which indicate NMDA receptor antagonistic function of tryptophan metabolites, mice with various genetic modifications of tryptophan catabolism and consecutive changes in calcium signalling will be investigated. By combining patch clamp analyses with the use of calcium sensitive dyes, disturbances in calcium homeostasis in endothelial cells will be studied.

The use of genetic and pharmacological modulation of tryptophan catabolism will further allow their impact on endothelial cell calcium signals and resultant T cell migration in vitro and in vivo, as well as disease activity and neurodegeneration in experimental autoimmune encephalomyelitis to be investigated. Interactions exist with project 1 (Diem/Flockerzi; Neurology Heidelberg/Pharmacology Homburg) on BBB dysfunction in mice lacking subunits of VDCCs and with projects 4 and 9 (Winkler/Williams; Neurology Heidelberg; Kirchhoff; Physiology Homburg), providing technical support for live imaging of BBB dysfunction at different lesion sites. Further planned collaborations include project 2 (Freichel/Friese; Pharmacology Heidelberg/ Neuroimmunology Hamburg) to investigate in vivo calcium channel functions and project 6 (Niemeyer/Alansary; Biophysics Homburg) to analyse calcium signals during activation of T cells in response to amino acid metabolites.

PrincipalInvestigators

Publications

Bittner S, Bobak N, Herrmann AM, Gobel K, Meuth P, Hohn KG, Stenner MP, Budde T, Wiendl H, Meuth SG (2010) Upregulation of K2P5.1 potassium channels in multiple sclerosis. Ann Neurol 68:58-69

Bittner S, Ruck T, Schuhmann MK, Herrmann AM, Moha ou Maati H, Bobak N, Gobel K, Langhauser F, Stegner D, Ehling P, Borsotto M, Pape HC, Nieswandt B, Kleinschnitz C, Heurteaux C, Galla HJ, Budde T, Wiendl H, Meuth SG (2013) Endothelial TWIK-related potassium channel- 1 (TREK1) regulates immune-cell trafficking into the CNS. Nat Med 19:1161-5

Göbel K, Schuhmann MK, Pankratz S, Stegner D, Herrmann AM, Braun A, Breuer J, Bittner S, Ruck T, Wiendl H, Kleinschnitz C, Nieswandt B, Meuth SG (2014) Phospholipase D1 mediates lymphocyte adhesion and migration in experimental autoimmune encephalomyelitis. Eur J Immunol 44:2295-305

Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B, Litzenburger UM, Sahm F, Ott M, Iwantscheff S, Grabitz C, Mittelbronn M, von Deimling A, Winkler F, Meuth SG, Wick W, Platten M (2013). Endothelial protein kinase Cβ as a therapeutic target stabilizing blood brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 110:14735-40

Meuth SG, Herrmann AM, Simon OJ, Siffrin V, Melzer N, Bittner S, Meuth P, Langer HF, Hallermann S, Boldakowa N, Herz J, Munsch T, Landgraf P, Aktas O, Heckmann M, Lessmann V, Budde T, Kieseier BC, Zipp F, Wiendl H (2009) Cytotoxic CD8+ T cell-neuron interactions: perforin- dependent electrical silencing precedes but is not causally linked to neuronal cell death. J Neurosci 29:15397-409

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197-203

Ott M, Litzenburger UM, Rauschenbach KJ, Bunse L, Ochs K, Sahm F, Pusch S, Opitz CA, von Deimling A, Wick W, Platten M (2014) Suppression of TDO-mediated tryptophan catabolism in glioblastoma cells by a steroid-responsive FKBP52-dependent pathway. Glia 63:78-90

Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM, Gupta R, Lee LY, Kidd BA, Robinson WH, Sobel RA, Selley ML, Steinman L (2005) Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310:850-5

Platten M, Wick W, van den Eynde B (2012) Tryptophan catabolism in Cancer: Beyond IDO and tryptophan depletion. Cancer Res 72:1-6

Sahm F, Oezen I, Opitz CA, Radlwimmer B, von Deimling A, Ahrendt , Adams S, Bode HB, Guillemin GJ, Wick W, Platten M (2013) The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer Res 73:3225-34

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Endothelial calcium signals in the control of neuroinflammation and neurodegeneration

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Prof. Dr. Dr.

Sven Meuth

Prof. Dr.

Michael Platten