PICTURE BY MAURICIO ROSAS-BALLINA, COURTESY OF KEVIN TRACEY
Neurotransmitters may play a bigger role in immunity than scientists had realized. In two papers published today (September 15) in Science Express, immunologists identify neurotransmitters as key players in two previously mystery-shrouded defense mechanisms: how the nervous system body puts the brakes on an overenthusiastic inflammatory response, and the reasons behind post-stroke infections.
“These connections between the brain and immune system in both health and disease are very intriguing,” said Lawrence Steinman, a professor of neurology at Stanford School of Medicine who was not involved in the study. The findings could have implications for the treatment of inflammatory disorders and stroke patients, he added.
The immune system is designed to protect the body from infection and injury, but an overactive immune response can damage organs or lead to inflammatory diseases. The vagus nerve connects the brain to the body and controls inflammatory response. One molecule in particular, the neurotransmitter acetylcholine, is released by the vagus nerve to slow the immune response before it causes collateral damage. In the spleen, for example, acetylcholine is necessary for blocking the production of dangerous amounts of inflammatory molecules like cytokines, but the details of how it worked was unclear.
Kevin Tracey, an immunologist at the Feinstein Institute for Medical Research in Manhasset, New York, discovered the “missing piece” for how the vagus nerve orchestrates immunity. Tracey and colleagues found that T cells in mouse spleens are actually releasing acetylcholine themselves after receiving a signal from the vagus nerve, playing a critical role in blocking inflammation. Though T cells are part of the immune system, in this context they’re essentially functioning as a neuron, Tracey said. “It’s remarkable.” Though the idea that immune cells can make neurotransmitters is not a new story, Tracey added, no one has ever shown that nerve signals initiate their release, and in turn play a protective anti-inflammatory role against disease.
The more researchers understand about the functioning of this circuit, the more they can apply their knowledge for treating and preventing disease, said Tracey, who in 2006 co-founded SetPoint Medical, a company that investigates ways to manipulate the vagus nerve to treat diseases like rheumatoid arthritis. “Modulating the immune system with pharmacologic reagents or with medical devices that stimulate the vagus nerve could offer real promise in inflammatory conditions,” agreed Steinman.
Neurotransmitters also seem to be playing a role in the immune response of the brain. Specifically, the immune suppression commonly seen in stroke victims, which is believed to prevent further inflammation-induced damage to the brain, appears to be regulated by a noradrenergic neurotransmitter.
In experiments with mice, immunologist Paul Kubes of the University of Calgary and his colleagues examined the behavior of natural killer T cells in the liver following a stroke. Rather than being controlled by normal danger signals like CD1d ligands or cytokines that alert the NKT cells to infection, the researchers found that a noradrenergic neurotransmitter—known to control the sympathetic nervous system’s flight of fight reflex—was the immune-suppressing culprit.
Normally T cells patrol the liver, referred to as intravascular crawling. Following a stroke, inhibitory pathways are activated to cause immunosuppression, though the underlying mechanisms were elusive until now. After inducing injuries in mice, the researchers found that brain damage, but not injuries to a limb, caused the NKT cells to stop their locomotion throughout the liver. Adding noradrenalin to cultured NKT cells similarly halted the cells’ normal liver patrolling behavior, mimicking the cells’ post-stroke in vivo movement in mice. Blocking noradrenalin, on the other hand, allowed the cells to resume their regular movements, suggesting the neurotransmitter was essential to NKT cell behavior.
The results have important implications for post-stroke care, said Kubes, as stroke patients often fall ill from infections during this period of immune suppression. Indeed, when the researchers blocked neurotransmitters, the mice were less likely to succumb to an infection after a stroke. They found a similar result after treating the NKT cells with an immunostimulant, demonstrating that either directly modulating NKT cells or blocking noradrenergic neurotransmitters to stimulate immunity could hold therapeutic potential for immunosuppressed stroke victims.
Helping stroke victims will entail a delicate balance between an overactive immune system (which could damage the brain) and a muted one (which allows for infection), Kubes said. “If we could maintain the inflammatory sentinels’ abilities to watch for enemy bacteria, I think we could probably help many patients.” Steinman agreed that there is potential for immune-modulation therapy in the future for stroke victims, adding that several groups are currently looking into similar questions.
M. Rosas-Ballina, et al., “Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit,” Science Express, doi:10.1126/science.1209985, 2011.
C. H. Y. Wong, et al., “Functional Innervation of Hepatic iNKT cells Is Immunosuppressive Following Stroke,” Science Express, doi:10.1126/science.1210301, 2011.