Fueling the fire in the lung-brain axis: The salience network connects allergen-provoked TH17 responses to psychological stress in asthma

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.