The Neuro-immune Synapse

A synapse is a connection between nerves, or possibly even a connection between a synapse and a white cell, as it now turns out.

The term “neuro-immune synapse” was first introduced to us by Dr. Carl Saab. When Dr. Saab (Brown) says something we do not argue, but merely fall in line. He has been bullseyeing pain principles, however controversial, even before graduating as did Bryan Hain (Yale) from the amazingly productive pain research program headed by Claire Hulsebosch at UTMB, with the progeny of that program now becoming a brain trust on nerve injury pain throughout the United States.

It is probably not an exaggeation to say that Dr. Saab’s highly contested but now proven report that the vermis of the cerebellum is involved in pain inhibition woke up the neuroradiologists like nothing ever had. The very notion of “seeing” pain was astonishing. Now we are finding even tensor MRI being used to study neuropathic pain. You see, pain has not always been legitimate. Why play to the “weak”, was the idea. Despite all the efforts to bury pain as imaginary it keeps popping up in the most embarassing places to demonstrate that pain patients really are suffering.

How this information was suppressed can only be explained by the impotence to help it by clinicians. Central Pain was as welcome as an illegitimate child to royalty and denial the only defense against the accusation that doctors were ignoring desperately ill people. Some die hard clinicans are still holding out for the pain is psychological theory, thus avoiding the admission of years of abusing the sick, but no self respecting PhD in neurochemistry would dare question nerve hypersensitization now. Hypersensitization is the very core of PhD pain research at the present time.

“Neuroimmune synapse” seemed odd at first, since synapse traditionally has referred to the body’s more or less connected neurons. It may not be that simple. It now appears possible that an immune cell may somehow connect to a synapse, using some of the same adhesion molecules which traditionally have been thought to be the exclusive parts of a neuron t neuron synapse. That cell would be an immune cell of some kind, perhaps a white cell, a microglial cell, or other yet to be selectively named cell. What do we call such a hybrid. Should we use the term “synapse” which by existing theory ought to be an oxymoron, or should we say, “synapse-like connection” since it is undeniably present.

Dr. Saab has questioned what is the signal occurring at the neuro-immune synapse. Two prior articles described the importance of cell adhesion proteins. We saw how TNF could be blocked by other cells. The question almost reduces to whether the body’s immune system would prefer to dissolve or kill (apoptosis) damaged neurons to PREVENT the development of nerve injury pain, whether successful immune actions act otherwise to preserve injured neurons, or whether the continual attempt to accomplish an immune function spawns the cascade of pain exciters.

Suzuki et al at Nagoya, in Biol Pharm Bull. 2004 Dec;27(12):1891-4 irreversibly legitimized the idea by reporting that N-cadherin plays a role in the synapse-like structures between mast cells and neurites (a neurite is any extension of a nerve cell body, such as a dendrite or axon). The very concept is radical–a connection between nerves and mast cells sugggests an entirely new way of looking at things. Mast cells are immune functioning cells, found ,among other places, in the brain. Mast cell derived mediators can affect neuronal function.

The authors state “the molecules involved in the membrane-membrane contacts between nerves and mast cells are still unknown. Here, we used an in vitro co-culture approach comprising interaction between immune (bone marrow-derived mast cell, BMMC) and nerve cells (superior cervical ganglia, SCG). The experiments showed clearly that the nerve-mast cell communication was supported by synapse-like structure and that N-cadherin, not E-cadherin, played an essential role in the synapse-like structure. In addition, we found that the synapse-like structure was assisted by clustering of beta-catenin to N-cadherin.”

Do not be discouraged by terms such as cadherin and catenin, These are long known molecules which exist in or around any synapse. What you should focus on is the term “synapse-like structure”. You would not be reading this awkward term if scientists had any idea what it really was. It visually looks like a synapse but it theoretically shouldn’t be there because synapses are supposed to be between two neurons, but here we see cadherin and catenin, two clearly synaptic molecules related to the structural integrity of a synapse, appearing to help bind a mast cell to a nerve cell. This is breaking new territory.

Suggestion of a neuro-immune synapse had been previously reported by Tournier and Hellman in Trends Immunol. 2003 Mar;24(3):114-5.

Making life interesting was the early report by Vizi and Elenkov in Acta Biol Hung. 2002;53(1-2):229-44 on NON synaptic
noradrenaline release in neuro-immune responses. These authors allege evidence that the sympathetic nervous system regulates cytokine production. Cytokines are chemicals which are part of central pain and other processes. Here, we are referring to their drawing of immune cells to the central nervous system. If you prefer, you can loosely associate the words, “pro-inflammatory cytokines” with acid in the synapses, which is the result, remembering that the vacuoles around a synapse are pH dependent. Tissues involved in immune responses are said to be activated by noradrenaline which comes from varicose axon terminals of sympathetic nerve cells. (the varicose terminal just means an active type of connection from a neuron to a synapse–the varicosity suggests activity)

The authors state “In our laboratory convincing evidence has been obtained that NA released non-synaptically [90, 92] from sympathetic axon terminals and enhanced in concentration in the close proximity of immune cells is able to inhibit production of proinflammatory (TNF-alpha, IFN-gamma, IL-12, IL-1) and increase antiinflammatory cytokines (IL-10) in response to LPS [25, 91], indicating a fine-tuning control of the production of TNF-alpha and other cytokines by sympathetic innervation under stressful conditions. This effects are mediated via beta2-adrenoceptors expressed on immune cells and coupled to cAMP levels.”

Whether or not Vizi is correct that the connection is nonsynaptic or whether the nonsynaptic connection soon leads to a “synapse-like structure” is likely to show these processes, by whatever name, are clearly related.

Understanding the neuroimmune synaptic connections is going to be very important in regulating how TNF alpha impacts the synapse of injured cord and hopefully in illuminating how to stop central pain. We thank all the scientists who are working on this and Dr. Saab for emphasizing its deserving a description at this point.