TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system.
We provide evidence that TWIK-related acid-sensitive potassium channel 1 (TASK1), a member of the family of two-pore domain potassium channels relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation. After induction of experimental autoimmune encephalomyelitis, an experimental model mimicking multiple sclerosis, TASK1(-/-) mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls. T cells from TASK1(-/-) mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal. In addition to these effects on systemic T cell responses, TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves. Anandamide, an endogenous cannabinoid and inhibitor of TASK channels, reduced outward currents and inhibited effector functions of T cells (IFN-gamma production and proliferation); an effect completely abrogated in TASK1(-/-) mice. Accordingly, preventive blockade of TASK1 significantly ameliorated experimental autoimmune encephalomyelitis after immunization. Therapeutic application of anandamide significantly reduced disease severity and was capable of lowering progressive loss of brain parenchymal volume as assessed by magnetic resonance imaging. These data support the identification and characterization of TASK1 as potential molecular target for the therapy of inflammatory and degenerative central nervous system disorders.
Bittner
Stefan
S
University of Wuerzburg, Department of Neurology, Josef-Schneider-Str. 11, 97080 Wuerzburg, Germany.
Meuth
Sven G
SG
Göbel
Kerstin
K
Melzer
Nico
N
Herrmann
Alexander M
AM
Simon
Ole J
OJ
Weishaupt
Andreas
A
Budde
Thomas
T
Bayliss
Douglas A
DA
Bendszus
Martin
M
Wiendl
Heinz
H
D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use; D001369:Axons / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D063388:Endocannabinoids; D005260:Female; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D009410:Nerve Degeneration / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000276:immunology*; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D046509:Tissue Culture Techniques
D001095:Arachidonic Acids; D063388:Endocannabinoids; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; C078814:anandamide