Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms.

Stefan Bittner,Heinz Wiendl,Tobias Ruck,Michael Schuhmann,Nicole Bobak,Majella-Sophie Hofmann,Sven Meuth,Kerstin Göbel,Wolfgang Brück

doi:10.3390/ijms160816880

Abstract

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K2P5.1 knockout (K2P5.1−/−) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K2P5.1−/− mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K2P3.1 and KV1.3 seems to counterbalance the deletion of K2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K2P5.1-targeting drugs.

Highlights

Ion channels have long been established as important regulators of the physiological functions ofT lymphocytes and other immune cells [1]
WT and K2P5.1−/− mice were immunized with MOG35–55 peptide in order to induce EAE, an animal model mimicking aspects of multiple sclerosis (MS)
Our current findings demonstrate that K2P5.1−/− mice show no obvious phenotype in autoimmune neuroinflammation due to a functional compensation by the potassium channels K2P3.1 and KV1.3

Summary

Introduction

Ion channels have long been established as important regulators of the physiological functions ofT lymphocytes and other immune cells [1]. Ion channels have long been established as important regulators of the physiological functions of. Targeting of potassium channels as a potential therapeutic strategy for autoinflammatory disorders can nowadays be viewed as an established concept, and the first attempts for clinical trials are ongoing [3,4,5]. Human and murine T lymphocytes express the K2P channels K2P3.1 (TASK1; KCNK3), K2P5.1 (TASK2; KCNK5) and K2P9.1 (TASK3; KCNK9) [1,4,7]. All three K2P channels are involved in T cell functions, such as proliferation or cytokine production [7,10]. Expression of K2P5.1 is increased following T cell activation and in pathogenic T lymphocytes from patients with MS [10] and rheumatoid arthritis (RA) [11]. An especially pronounced upregulation of K2P5.1 was found on T lymphocytes located in the cerebrospinal fluid of MS patients and in the synovial fluid of RA patients, respectively [10,11]

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