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.

Macrophages, known as the “Big Eaters” are populations of immune cells that protect the body against various pathogens by engulfing them, by secreting various chemicals to let the other components of the immune system know that the body is under attack, and also by causing inflammation.  The macrophages inside the central nervous system are called “microglia”.  Glia are cells in the central nervous system that are not neurons but are involved in maintaining the function of neurons.  Specifically, glial cells are involved in providing a proper chemical environment for the neurons so that they can communicate properly.  For example, glial cells provide nutrition, physical support, and contribute to production of myelin.  Microglia comprise approximately 20% of the glial cell population.  Other glial cells include astrocytes (that amongst other things physically connect neurons to their blood supply) and oligodendrocytes (which make myelin).

While microglia are normally involved in protecting the brain from infections, they also are believed to play a pathological role in multiple sclerosis.  For example, microglial production of inflammatory cytokines, free radicals, and matrix metalloproteases is believed to be one of the reasons why multiple sclerosis damages the central nervous system (Benveniste et al. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 1997 Mar;75(3):165-73).  This makes sense in some ways since T cells producing the cytokine interleukin-17 (IL-17), called Th17 cells, have been found both in mice and humans with multiple sclerosis.  Interestingly, microglia express receptors for IL-17, and the level of receptor expression increases during disease induction (Das Sarma et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 2009 Apr 28;6:14).  On the flip side of the coin, microglial cells have been postulated to also be involved in repair of the brain during multiple sclerosis (Napoli and Neumann.  Protective Effects of Microglia in Multiple Sclerosis. Exp Neurol. 2009 May 3).

Macrophages are interesting cells.  As we discussed previously in the same why that T cells may be effector T cells and T regulatory cells, broadly speaking, so too macrophages may be proinflammatory (called M1) and antiinflammatory (called M2).  In fact, one of the reasons why using your own fat stem cells may be therapeutically beneficial in multiple sclerosis is because there are high concentrations of antiinflammatory M2 macrophages found in the fat.  The classical distinction between these two types of macrophages has been that M1 macrophages produce nitric oxide when they are activated and that M2 macrophages produce products of the enzyme arginase.  Mesenchymal stem cells, which have demonstrated activity against the mouse model of multiple sclerosis, have been demonstrated to be able to induce an M2-like phenotype in macrophages by stimulating them to produce the antiinflammatory cytokine interleukin-10.  Before we continue, we should state that macrophages are derived from monocytes, and there is some work suggesting that monocytes in special situations may act as stem cells.

Now if mesenchymal stem cells have the ability to induce production of interleukin-10 in macrophages, what if someone discovered a chemical that could induce production of this antiinflammatory cytokine (which theoretically would be beneficial for multiple sclerosis) simply by administration of the chemical?  While this would not induce the regenerative or growth factor effects of mesenchymal stem cells, it may be useful for inhibiting the destruction cause by activated macrophages. 

A recent paper (Correa et al. Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: Roles of ERK1/2, JNK, and NF-kappaB. Glia 2009 Jun 29) demonstrated that the endocannabinoid anandamide may actually have this property.

Anandamide a neurotransmitter of the cannabinoid family that occurs naturally in the human central nervous system.  It activates the CB1 receptor in the brain and the CB2 receptor in the periphery.  It is known that activation of cannabinoid receptors is associated with decreased symptoms in animal models of multiple sclerosis (Cabranes et al. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol Dis 2005 Nov;20(2):207-17).  It is also known that deletion of the enzyme Fatty Acid Amide Hydrolase (FAAH), whose role is to metabolize anandamide, causes regression of symptoms of multiple sclerosis in animals, presumably by increasing the amount of endogenous anandamide (Webb et al. Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis. Neurosci Lett. 2008 Jul 4;439(1):106-10).  Therefore in the paper that we are discussing, the investigators wanted to see if anandamide may alter production of cytokines and behavious of microglial cells.

The authors demonstrated that administration of anandamide results in upregulation of interleukin-10 production from microglial cells that have been activated.  The induction of interleukin-10 seemed to be associated with suppression of the transcription factor NF-kB, which is involved in numerous inflammatory conditions.  Furthermore, the investigators demonstrated that microglial cells treated with anandamide had suppressed ability to produce the inflammatory cytokines IL-12 and IL-23, which was correlated to inhibition of Th1 and Th17 generation.

These data suggest a very important point, which is that numerous neurotransmitters may have effects on immunological cells.  Theoretically, this should not be that surprising.  The immune system and the nervous system are the only systems of the body that share the features of: a) Distinguishing between what is self and what is non-self; b) Ability for specificity; c) Memory; and d) Innate reactivity.  At a practical level, the major immunological organs such as they thymus and spleen are highly innervated.  Additionally, most immunological cells, including dendritic, T cells, B cells, and NK cells all have expression of receptors for neurotransmitters. 

Therefore we at Stemnow.com believe that this area of “neuroimmunology” will be an exciting one to watch in the upcoming years.