A new study on a mouse model of asthma shows that nerve cells producing dopamine, a neurotransmitter, signal T cells in the body to promote inflammation due to allergic reactions in the lungs during childhood but not in adult mice. The study, published in the journal Immunity on November 19, 2019, could explain why children are more prone to asthma than adults are, and could also help develop new methods of treating this illness.
Harvard researcher Xingbin Ai says, “This is the first study that reveals a contribution of age-related nerve-T cell communication to susceptibility to the development of asthma in young children.” The scientist goes on to explain that understanding how the disease is brought about in young children will help to identify new areas that can be targeted to prevent the development of asthma in early childhood – a very common occurrence.
Boy using an asthma inhaler. Image Credit: Wavebreakmedia / Shutterstock
Asthma is a condition in which the airways become inflamed and narrow from time to time, limiting air flow to various degrees. This phenomenon is called bronchospasm, and the patient complains of wheezing, tightness in the chest, shortness of breath, and cough. In between episodes, the patient is characteristically normal.
Asthma is not only distressing and limiting with respect to physical activity but can endanger life if the airway narrows so much that it closes off almost completely. In many cases, environmental triggers such as pet dander or insect body parts can be identified and managed, along with drugs to relieve the bronchospasm. However, there is no cure, and asthma continues to be among the most common childhood illnesses.
The current study was designed to explore the involvement of the nervous system in childhood asthma. The researchers suspected this scenario because the nervous system is known to develop even after the child is born, and thus at different ages, the nervous system may react to or influence inflammation within the tissues in a different manner.
To explore nerve-inflammation connections, the researchers investigated the types of neurons in the developing nervous system, in mice with very early-onset asthma. They found that immediately after birth, the sympathetic nerves that supply the mouse lung are mostly dopaminergic. However, as the mice mature into adults, these same nerves begin to produce norepinephrine.
They then compared lung tissue and tissue from lymph nodes, retrieved from children aged 0-13 years, as well as from adults aged 40-65 years. They found the same type of innervation.
Next, they looked at the fate of this dopamine released by the sympathetic nerve fibers. They found that this molecule was bound to dopamine receptors on T helper cells carrying an antigen called CD4+. This resulted in the increased differentiation of these cells into type 2 T helper cells (Th2) which promote lung inflammation, worsening asthmatic changes.
In adults, there was no similar effect, probably because at this age the nerves produced norepinephrine.
The scientists found that when new-born mice were exposed to allergens, dopaminergic DRD4 signaling occurred, enhancing Th2 cell-mediated inflammatory changes in the lung tissue. This was shown in the form of increased mucus production within the airways, which were hyper-reactive to allergens and inflammatory signals. These changes were not seen or were much less significant when adult mice were studied in the same exposure situation.
The scientists concluded that the dopamine-DRD4 signaling pathway links sympathetic nerves to the CD4+ Th cells within the lung tissue, aggravating allergic inflammation in very early childhood. The advantage of this pathway at this age could be that the active inflammatory response causes the release of other growth factors, which allows the lung tissue to repair itself following infection. This feature is very important for an immature tissue that can easily be infected.
The study is also important in that it shows that mice and humans are similar in the way dopaminergic fibers supply the early lung tissue, and how T cells respond to dopamine.
When it comes to using these findings to treat or prevent early childhood asthma, Ai cautions that wholesale blocking of the dopamine-DRD4 signaling system is an ill-conceived notion. Many researchers have shown that such non-targeted interventions result in off-target effects which can be very serious. He points out, “Nerves play important roles in regulating functions of the airway, such as breathing. We will need to identify more specific pathways along the nerve-immune cell axis for therapeutic targeting.”
The team now wants to discover which molecules in this pathway can be modulated or inhibited by drugs in order to disable the dopamine-DRD4 pathway when it becomes overactive on exposure to an allergen. They also want to find out if this pathway, that changes with age, is related in any way to the progression of asthma from childhood to adult life. If so, they will examine if they can keep this progression from occurring. Finally, they hope to explore how exposure to allergens or to viruses alter the development mode of nerves supplying the lung tissue, to activate asthmatic responses in early childhood.
Such detailed studies may provide biomarkers that specifically pick out allergic asthma in children as well as helping to predict the course and severity of the illness. Biomarkers are molecules that can be tested for in blood or tissue samples. Ai also looks forward to more successful therapy for allergic childhood asthma, saying, “Targeting the communication between sympathetic nerves and CD4+ T cells via the dopamine-DRD4 pathway may be a strategy to battle the increasing prevalence of allergic asthma in children.”
Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung Wang, Wei et al. Immunity, https://www.cell.com/immunity/fulltext/S1074-7613(19)30446-7