In the mouse vagal ganglion, sensory neurons labeled from the auricular skin (green) and the lung (magenta) are located in close proximity (white circles). These findings suggest a possible anatomical basis for how sensation from the auricular skin may influence airway immune responses via nerves that directly supply the lung.
Image Credit: Rintaro Shibuya, Kim Lab, Icahn School of Medicine at Mount Sinai.
Scientific Frontline: Extended "At a Glance" Summary: Auricular Vagus Nerve Stimulation
The Core Concept: The stimulation of the auricular vagus nerve in the external ear can alleviate lung inflammation through a newly identified neuroimmune reflex linking the skin and the respiratory system.
Key Distinction/Mechanism: Rather than relying on traditional pharmacological anti-inflammatory drugs, this approach utilizes targeted bioelectronic stimulation of the cymba conchae in the outer ear. This physical stimulation increases the release of the neurotransmitter protein CGRPβ in the airways, which actively reduces lung inflammation, whereas inhibiting these nerve fibers exacerbates airway disease.
Major Frameworks/Components:
- Neuroimmunology: The foundational study of the bidirectional interactions between the nervous and immune systems.
- Vagal Homeostasis: The overarching physiological framework positioning the vagus nerve as a master regulator (or "rheostat") of organ function and inflammation.
- Auricular Vagus Nerve: The unique, superficial branch of the vagus nerve accessible via the skin of the external ear.
- Neurotransmitter CGRPβ: The specific protein upregulated in the airway upon nerve stimulation, responsible for mitigating the inflammatory response.
- Optogenetics and Chemogenetics: The advanced biological methodologies utilized in murine models to safely isolate and manipulate specific nerve pathways during the study.
Branch of Science: Neuroimmunology, Neuroscience, Immunology, and Pulmonology.
Future Application: The ongoing development of novel, noninvasive bioelectronic devices and targeted neuroimmune therapies for managing asthma, pulmonary fibrosis, inflammatory bowel disease, and rheumatoid arthritis.
Why It Matters: This discovery reveals a previously unknown, non-pharmacological mechanism to control systemic inflammation, offering a precise, anatomical approach to treating chronic and debilitating immune-mediated diseases by leveraging the body's hardwired nervous system.
Neuroimmunology, the study of interactions between the nervous and immune systems, is a rapidly growing field enabling new approaches for monitoring and treating inflammatory diseases. In a recent study, scientists showed that in mice, stimulating a nerve in the external ear may help ease inflammation in the lungs. Based on these findings, the researchers are designing a clinical trial to test a novel device for treating asthma.
"We are always looking for new therapeutics and devices that can kick-start the body and get it back to doing what it needs to do," says senior and corresponding author Brian S. Kim of the Icahn School of Medicine at Mount Sinai in New York. "This research suggests a new way to target the body's inflammatory pathways."
Neuroimmunology took off after research revealed how the vagus nerve—the "information superhighway" that connects the brain to major organs and controls their functions—helps regulate the immune system.
"The vagus nerve is hardwired to be a homeostatic organ," says Kim. "You can think of it like a rheostat that integrates everything and keeps it in check."
For this study, the authors leveraged the unique characteristics of the auricular vagus nerve, the only branch of the vagus nerve that reaches the surface of the skin. This nerve is found in the cymba conchae, the small, bowl-shaped depression in the upper part of the outer ear.
"Given the strong connection between the lungs and the vagus nerve, we sought to use the lungs as a test case to study these mechanisms and see whether manipulating the auricular branch could modulate inflammation," says Kim.
The team studied these connections in mouse models using several approaches, including chemogenetics and optogenetics, to see what happened when the auricular vagus nerve was stimulated in the presence of an allergen. Their work showed that stimulation of the nerve increased levels of a neurotransmitter protein called CGRPβ in the airway. This, in turn, reduced inflammation in the lungs. When the nerve fibers were instead inhibited, airway disease was exacerbated.
"Our findings reveal a previously unrecognized neuroimmune reflex linking the skin and the lungs," says first author Rintaro Shibuya of Kyoto University. "I hope this work inspires new ways of thinking about vagus nerve biology and future bioelectronic and neuroimmune therapies for inflammatory diseases."
Although the research is in its early stages, the team says this approach has many potential applications for treating diseases characterized by inflammation, including pulmonary fibrosis, inflammatory bowel disease, and rheumatoid arthritis.
"We still don’t know the extent to which the effects of stimulating the auricular vagus nerve go beyond the airway, but it’s something we will continue to study in the lab," says Kim.
Published in journal: Immunity
Title: Activation of the auricular vagus nerve reflex suppresses airway inflammation
Authors: Rintaro Shibuya, Nobuya Abe, Keaton Song, Nathan D. Rossen, Masato Tamari, Zhen Wang, Zili Xie, Yuki Abe, Hisato Iriki, Ayana Iijima, Lydia Zamidar, Xu Li, Xia Meng, Andras Bimbo-Szuhai, Veronica Burstein, Jill K. Gregory, Natalia P. Biscola, Karen Anthony, Michel Enamorado, Steven J. Van Dyken, Kenji Kabashima, Hongzhen Hu, and Brian S. Kim
Source/Credit: Kyoto University
Edited by: Scientific Frontline
Reference Number: ns071626_01