Title: Fueling the fire in the lung-brain axis: The salience network connects allergen-provoked TH17 responses to psychological stress in asthma
Legend: A) Within-subject study design (n = 28 adults with asthma). Brain glucose metabolism was measured using [18F]fluorodeoxyglucose positron emission tomography (PET) during a psychosocial stress test, compared to a non-stressful control task, during which salivary cortisol was collected. Airway inflammation was assessed before and after whole-lung allergen challenge. This design uniquely probes efferent brain-to-lung pathways.
B) Cortisol was associated with glucose metabolism in a widespread pattern following stress, relative to the control condition. Regions included local peaks in the amygdala, insula, and dACC. Yellow = all voxels showing a significant positive correlation with the magnitude of stress-evoked cortisol; Red = local salience network peaks.
C) Differential glucose metabolism (stress-control) in the amygdala and dACC predicted IL-23A mRNA expression following stress, relative to the control condition. Clusters in the right and left amygdala and dACC where glucose metabolism correlated with IL-23A mRNA expression, in the stress condition compared to the control condition
Citation: Higgins, E. T., Busse, W. W., Esnault, S., Christian, B. T., Klaus, D. R., Bach, J. C., Frye, C. J., & Rosenkranz, M. A. (2025). Fueling the fire in the lung-brain axis: The salience network connects allergen-provoked TH17 responses to psychological stress in asthma. Brain, behavior, and immunity, 128, 276–288. https://doi.org/10.1016/j.bbi.2025.04.004
Abstract:
Background – Asthma, a highly prevalent chronic inflammatory disease of the airways, results in an average of 10 deaths per day in the U.S., and psychological stress hinders its effective management. Threat-sensitive neurocircuitry, active during psychological stress, may intensify airway inflammatory responses and contribute to poor clinical outcomes. However, the neural mechanisms and descending pathways connecting acute stress and inflammatory responses to allergen exposure remain poorly understood. We hypothesized that stress-induced engagement of the salience network would prime Th17 immune pathways and potentiate airway inflammation.
Methods – We measured brain glucose metabolism during the Trier Social Stress Test (TSST) and a non-stressful control task using [18F]fluorodeoxyglucose positron emission tomography (PET) in 28 adults (18F) with asthma. Salivary cortisol was collected to quantify physiological stress responses. Before and after airway provocation with a whole-lung allergen challenge (WL-AG), airway inflammation was assessed using fraction of exhaled nitric oxide (FeNO), sputum % eosinophils, and expression of Th17-related cytokine mRNA in the airway.
Results – As expected, the WL-AG increased all inflammatory biomarkers. Acute stress significantly increased salivary cortisol (t(27.3) = -27.3, p < 0.01), but did not significantly affect airway inflammation overall. Instead, more robust cortisol responses to stress predicted increased glucose metabolism in the amygdala, insula, and dorsal anterior cingulate cortex, key nodes in the salience network, as well as increased IL-23A mRNA expression (t(22.1) = 2.38, p = 0.026) and FeNO (t(21.5) = 2.17, p = 0.041). Moreover, differential increases in amygdala and dACC glucose metabolism predicted differential increases IL-23A mRNA expression following WL-AG. In addition, compared to low chronic stress, high chronic stress was associated with enhanced IL-17A mRNA expression in response to acute stress and WL-AG.
Conclusions – Individual differences in salience network and cortisol responses to acute stress predict enhanced allergen challenge-provoked Th17-related responses, advancing our understanding of the efferent arm of the lung-brain axis in asthma. This work underscores the importance of translational research for the development of novel interventions that target stress-sensitive brain and immune pathways.
Keywords: Acute stress, Asthma, Chronic stress, Cortisol, Inflammation, Neuroimaging, Th17
Investigator: Richard J Davidson, PhD
About the Lab: Research in Davidson’s laboratory is focused on the neural bases of disordered and healthy emotion and emotional style and methods to promote human flourishing, including meditation and related contemplative practices. His studies have included persons of all ages, from birth though old age, and have also included individuals with disorders of emotion, such as mood and anxiety disorders and autism, as well as expert meditation practitioners with tens of thousands of hours of experience. His research uses a wide range of methods, including different varieties of MRI, positron emission tomography, electroencephalography, and modern genetic and epigenetic methods.