Activated T-cells inhibit neurogenesis by releasing granzyme B: rescue by Kv1.3 blockers.
There is a great need for pharmacological approaches to enhance neural progenitor cell (NPC) function particularly in neuroinflammatory diseases with failed neuroregeneration. In diseases such as multiple sclerosis and stroke, T-cell infiltration occurs in periventricular zones where NPCs are located and is associated with irreversible neuronal loss. We studied the effect of T-cell activation on NPC functions. NPC proliferation and neuronal differentiation were impaired by granzyme B (GrB) released by the T-cells. GrB mediated its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltage-dependent potassium channel, Kv1.3. Importantly, blocking channel activity with margatoxin or blocking its expression reversed the inhibitory effects of GrB on NPCs. We have thus identified a novel pathway in neurogenesis. The increased expression of Kv1.3 in pathological conditions makes it a novel target for promoting neurorestoration.
Wang
Tongguang
T
Department of Neurology, The Johns Hopkins University, Baltimore, Maryland 21287, USA.
Lee
Myoung-Hwa
MH
Johnson
Tory
T
Allie
Rameeza
R
Hu
Lina
L
Calabresi
Peter A
PA
Nath
Avindra
A
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005333:Fetus; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D053804:Granzymes