Credit: Inok/iStock/Getty Images Plus.
By studying the formation of plaques in the arteries, a European research group, including Italian scientists, has revealed an unexpected connection between the circulatory, nervous and immune systems. As well as suggesting that atherosclerosis could be partly controlled by the brain, the study1 reveals a biological mechanism that may have a role in many other diseases.
Atherosclerosis is the process by which fatty substances circulating in the arteries can accumulate and form plaques. Over time, these plaques restrict the blood flow and oxygen supply to vital organs, increasing the risk of heart attacks and strokes. Currently, there are no treatments that can reverse the process.
The arteries have two sides: the intima layer — the internal wall where plaques initially form, and the adventitia — the external wall, where nerves run. While most research has focused on the intima, the authors of the new study looked at the role of the adventitia.
A team led by Andreas Habenicht, from the Ludwig-Maximilians University in Munich, had previously found that, as the disease progresses, immune cells infiltrate the arterial wall, forming aggregates that expand in the arterial tree. These cells develop into artery tertiary lymphoid organs (ATLOs), that resemble normal lymph nodes, though their cells are probably derived from the spleen, that are involved in many diseases.
“When looking in the adventitia layer [in the proximity of the ATLOs] we immediately found the endings of the peripheral nervous system,” says Habenicht. The logical consequence was to follow these peripheral nerves up to the central nervous system, so the team injected a neurotropic virus directly into the adventitia of mice. Within two days, the virus migrated, and the scientists could follow its path using an imaging technique called immunofluorescence. In the end, they proved that there is a structural artery-brain circuit (ABC) consisting of afferent neurons that carry sensory information from the adventitia to the brain, and efferent ones that carry instructions in the opposite direction.
In order to analyse the circuit’s role in developing plaques, the German team joined forces with Daniela Carnevale and Giuseppe Lembo from Sapienza University in Rome and the Neuromed Institute in Pozzilli, who had previously demonstrated a connection between the vagus nerve – the longest nerve in the body - and immune functions in the spleen.
By using ultrasound to measure plaques in vivo, the team in Italy was able to confirm that the density of nerve fibers near the plaques, as well as the activity of the vagus nerve, increased in parallel with the progression of the disease. They then disrupted the artery-brain circuit either with chemical or surgical methods. “When we cut the innervation, the ATLOs collapsed, followed by an inhibition of the plaque progression and a plaque stabilisation,” says Carnevale.
This multidirectional pathway involving arteries, immune cells, and the nervous system is a new paradigm that goes beyond vascular disease. “Because atherosclerosis is only one among many human diseases that has a local inflammatory component, the paper raises the possibility that other diseases may also have a functional bidirectional communication with the nervous system”, says David Dichek, a Professor of Medicine at the University of Washington, who was not involved in the study.
Habenicht explains that just as the atherosclerotic lesions talk to the brain, the central and peripheral nervous systems could in turn alter the course of atherosclerosis. Once the neurons responding to the periphery are identified, it could be possible to use drugs or pacemaker-type devices to modulate the brain control of the immune system.
