Journal Article

Murine K sub(2P) 5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K sub(2P) 3.1- and K sub(V) 1.3-Dependent Mechanisms

Hofmann, Majella-Sophie, Gobel, Kerstin, Bobak, Nicole, Bruck, Wolfgang, Bittner, Stefan, Ruck, Tobias, Wiendl, Heinz, Meuth, Sven G, Schuhmann, Michael K

2015

Overview

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K sub(2P) 5.1 (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, K sub(2P) 5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K sub(2P) 5.1 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 K sub(2P) 5.1 knockout (K sub(2P) 5.1 super(-) super(/) super(-)) 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, K sub(2P) 5.1 super(-) super(/) super(-) 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 K sub(2P) 3.1 and K sub(V) 1.3 seems to counterbalance the deletion of K sub(2P) 5.1. 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 K sub(2P) 5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K sub(2P) 5.1-targeting drugs.

• Subject: Callithrix