We have discuss previously that numerous nervous system molecules have immune modulatory effects. For example, the endocannabinoid anandamide is capable of converting microglial cells from secreting inflammatory compounds to producing antiinflammatory cytokines such as interleukin-10. Microglial cells generally cause pathology in multiple sclerosis through production of glutamate, as well as release of inflammatory agents. By inducing microglial cells to produce interleukin-10, mechanisms similar to those that mesenchymal stem cells use to control inflammation may be activated. Neurologically-associated molecules also may play a role in homing of stem cells. For example, the neurotransmitter Substance P has recently been shown to act as attractant of stem cells.
Here we discuss an interesting new way of modulating T cells so as to prevent onset and progression of an animal model of multiple sclerosis. The publication (Bittner et al. TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain 2009 Jul 1) discusses the role of TASK1 in T cell activity in the experimental allergic encephalomyelitis model.
What is TASK1?
TASK1 stands for “TWIK-related acid-sensitive potassium channel 1″, which is a the two-pore domain potassium channel family that is important for maintaining resting membrane potential and balancing neuronal excitability. TASK1 activity is inhibited by low pH and is activated by certain anesthetics… and It is also known as OAT1; TASK; TBAK1; K2p3.1; and KCNK3, with the official name being KCNK3 potassium channel, subfamily K, member 3.
In the publication it was demonstrated that mice made genetically deficient for the TASK1 gene were substantially resistant to induction of experimental allergic encephalomyelitis. Interestingly, T cells from the TASK1 knockout mice had an inhibited proliferative and cytokine response in vitro, suggesting the resistance to EAE may be associated with alterations on the T cell side and not just on the neuronal side. Conceptually, one may expect neurons from TASK deficient animals to be more resistant to damage due to possible role of TASK1 in induction of apoptosis. Indeed, the authors did demonstrate using in vitro isolated neurons from TASK1 deficient and wild-type neurons that a protective effect was observed associated with TASK1 deficiency.
Anandamide, which we previously described as having potentially beneficial effects on the mouse model of multiple sclerosis (EAE) by virtue of its ability to alter microglial production of inflammatory agents was demonstrated to inhibit TASK1 activity. In vitro administration of anandamide was shown to inhibit T cell production of inflammatory cytokines.
Perhaps most exciting from the pubication was that administration of anandamide was capable of inhibiting progression of EAE after disease onset was initiated.
It will be interesting in the future to try to tease out the effects of anandamide between activities on the T cells and activities on the microglia, which do not necessarily need to be exclusive. For example, one could envision a system where T regulatory cells may be selectively “reprogramming” microglia to reduce inflammatory activities. Or conversely, T regulatory cells may be generated in the central nervous system as a result of microglial presentation of self-antigen in the presence of interleukin-10 generated by the anandamide-reprogrammed microglia.
In conclusion, the current work supports further investigation into the TASK1 channel as a possible target for drug development in multiple sclerosis. Given that mesenchymal stem cells already have demonstrated therapeutic effects in multiple sclerosis but in mice and man, it will be interesting to see if co-administration of anandamide may enhance mesenchymal stem cell regenerative activity by modulating the local microenvironment.