Increased Susceptibility to Allergic Asthma with the Impairment of Respiratory Tolerance Caused by Psychological Stress

Abstract

Background: Bronchial asthma is characterized by type 2 T helper (Th2) cell inflammation, essentially due to a breakdown of immune tolerance to harmless environmental allergens. Etiologically, experiences of psychological stress can be associated with a heightened prevalence of asthma. However, the mechanisms underlying stress-related asthma development are unclear. In this study, we examined whether psychological stress increases susceptibility to allergic asthma by downregulating immune tolerance. Methods: Female BALB/c mice were sensitized with ovalbumin/alum, followed by ovalbumin inhalation. Ovalbumin inhalation induced immune tolerance before sensitization occurred. Some mice were exposed to restraint stress during tolerance induction or sensitization. Asthma development was evaluated by airway responsiveness, inflammation, cytokine expression, and IgE synthesis. Sensitization was evaluated by measuring proliferation and cytokine production by splenocytes. The effects of stress exposure on the numbers and functions of dendritic cells and regulatory T (Treg) cells in bronchial lymph nodes and spleens were evaluated. To investigate the role of endogenous glucocorticoid in inhibiting immune tolerance after stress exposure, we examined the effects of (i) a glucocorticoid-receptor antagonist administered prior to stress exposure, and (ii) exogenous gluco­corticoid (instead of stress exposure). Results: Asthmatic responses and Th2-biased sensitization, which were suppressed in tolerized mice, re-emerged in tolerized mice stressed during tolerance induction in association with decreased tolerogenic dendritic and Treg cell numbers. The effects of stress exposure on tolerized mice were abolished by administering a glucocorticoid-receptor antagonist and reproduced by administering exogenous glucocorticoid without stress. Conclusions: Our findings suggested that psychological stress can potentially increase allergic asthma susceptibility by inhibiting immune tolerance.

Maternal Separation as Early-Life Stress Causes Enhanced Allergic Airway Responses by Inhibiting Respiratory Tolerance in Mice

“…The mice were sensitized and made to inhale antigen, as described previously (Kawano et al 2018), after stress exposure and tolerization ( Fig. 1).…”

“…On PND 76, all mice were challenged with aerosolized OVA or saline. On PND 77 and PND 81, bronchoalveolar lavage fluids (BALFs) were obtained (Kawano et al 2018) and processed to measure cytokine content, total cell counts, and cell differentials. After centrifugation, BALF supernatants were stored at -80°C before performing enzyme-linked immunosorbent assays (ELISAs) to measure cytokine levels.…”

“…Before and immediately after MS-stress exposure on PND 17 and immediately after MS-stress exposure on PNDs 19 and 22, blood was collected from stressed and non-stressed mice as previously described (Kawano et al 2018). Plasma samples separated from blood were stored at −80°C for corticosterone concentration measurements using an enzyme immunoassay kit (Enzo Life Sciences, Farmingdale, NY) according to the manufacturer's protocol.…”

“…Further, an acute laboratory stressor was able to decrease the number of CD4 + Foxp3 + Treg cells in the peripheral blood of human subjects (Freier et al 2010). Our group previously demonstrated that the use of restraint as a psychological stressor in adulthood increased susceptibility to asthma by inhibiting the development of Treg cells in a murine model of allergic asthma (Kawano et al 2018).…”

<p>Care Is the Doctor’s Best Prescription: The Impact of Doctor-Patient Empathy on the Physical and Mental Health of Asthmatic Patients in China</p>

“…Many mental stressors, such as anxiety, disappointment, distress, anger, fear and depression can cause asthma. 1 At the same time, the quality of life of patients with asthma is reduced, and other psychological problems including depression, anxiety, mania, panic disorder, sleep disorder, and post-traumatic stress disorder can appear. 2 Therefore, it is extremely important to support the psychological health of patients with asthma.…”