TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system

TLDR

The study shows that TASK1, a two‑pore domain potassium channel expressed on T cells and neurons, regulates T‑cell immunity and neurodegeneration in autoimmune CNS inflammation. TASK1 exerts neuroprotective effects independent of systemic T‑cell responses, as demonstrated in brain slice and optic nerve models, and its inhibition by the endogenous cannabinoid anandamide suppresses T‑cell effector functions in a TASK1‑dependent manner. TASK1 deficiency or blockade reduces clinical severity, axonal degeneration, and brain volume loss in experimental autoimmune encephalomyelitis, while impairing T‑cell proliferation and cytokine production, supporting TASK1 as a therapeutic target for inflammatory and degenerative CNS disorders.

Abstract

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-γ 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.