Social Stress Enhances Allergen-Induced Airway Inflammation in Mice and Inhibits Corticosteroid Responsiveness of Cytokine Production

Abstract

Chronic psychosocial stress exacerbates asthma, but the underlying mechanisms remain poorly understood. We hypothesized that psychosocial stress aggravates allergic airway inflammation by altering innate immune cell function. The effects of stress on airway inflammation, lung function, and glucocorticoid responsiveness were studied in a novel in vivo murine model of combined social disruption stress and allergic sensitization. The effects of corticosterone were assessed on cytokine profile and glucocorticoid receptor activation in LPS-stimulated spleen cell cultures in vitro. Airway inflammation resolved 48 h after a single allergen provocation in sensitized control mice, but not in animals that were repeatedly exposed to stress before allergen challenge. The enhanced eosinophilic airway inflammation 48 h after allergen challenge in these mice was associated with increased levels of IL-5, GM-CSF, IgG1, thymus-activated and regulatory chemokine, TNF-α, and IL-6 in the airways and a diminished inhibition of these mediators by corticosterone in LPS-stimulated splenocyte cultures in vitro. Stress-induced reduction of the corticosteroid effects paralleled increased p65 expression and a decreased DNA-binding capability of the glucocorticoid receptor in vitro. Furthermore, glucocorticoid receptor mRNA and protein expression in the lungs of mice exposed to both stress and allergen was markedly reduced in comparison with that in either condition alone or in naive mice. Thus, exposure to repeated social stress before allergen inhalation enhances and prolongs airway inflammation and alters corticosterone responsiveness. We speculate that these effects were mediated at least in part by impaired glucocorticoid receptor expression and function.

Parental Stress Increases the Detrimental Effect of Traffic Exposure on Children's Lung Function

“…Emerging evidence suggests that social deprivation promotes the adverse effect of air pollution on respiratory health outcomes (20,33,34), and psychosocial stress associated with deprivation is one possible explanation for this effect (9,13,19,35,36). In this study markers of social deprivation (i.e., low socioeconomic status; lack of health insurance; and housing characteristics, such as secondhand smoke exposure, cockroaches in the home, and lack of air conditioning) were associated with higher household stress (Table 1).…”

Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis

“…inflammatory responses (31)(32)(33)(34)(35)(36), and antigen-presenting cell (APC) stimulation of adaptive immune responses (34,37,38), RSD can functionally desensitize the monocyte glucocorticoid receptor (GR) (39)(40)(41)(42)(43). In the present studies, we used genomicsbased strategies to dissect the cellular mechanisms of the leukocyte CTRA in observational studies of human social adversity and the RSD experimental mouse model to determine whether chronic social stress might induce a proinflammatory skew in the circulating leukocyte transcriptome through selective expansion of a specific subpopulation of immature, proinflammatory monocytes (Ly-6c high in mice, CD16 − in humans) (23,(44)(45)(46).…”

Expression of XBP1 in lymphocytes of the small intestine in rats under chronic social stress and modulation of intestinal microflora composition

“…In large measure, suppression of immunity is due to the well-known anti-inflammatory effects of GC hormones. CSS, however, is not always immunosuppressive, particularly, if the stressor induces a state of functional GC resistance [2]. While the common view has been that stress suppresses immune system activity due to the suppressive effects of stress-induced GC hormones, there are now multiple studies demonstrating that stressor exposure can also enhance the immune response.…”

“…While the common view has been that stress suppresses immune system activity due to the suppressive effects of stress-induced GC hormones, there are now multiple studies demonstrating that stressor exposure can also enhance the immune response. Exposure to the stressor increases both innate and adaptive components of the immune system [1,2]. Specific immunological changes that have been observed in mice following of CSS include: splenomegaly; elevated levels of circulating proinflammatory cytokines; enhanced expression of TLRs on bone marrow, blood, and splenic monocytes; and the development of functional GC resistance [3].…”

“…Specific immunological changes that have been observed in mice following of CSS include: splenomegaly; elevated levels of circulating proinflammatory cytokines; enhanced expression of TLRs on bone marrow, blood, and splenic monocytes; and the development of functional GC resistance [3]. For example, the production of cytokines (e.g., TNF-α and IL-1β) is increased in LPS-stimulated splenic macrophages from mice exposed to the CSS [2,3]. In addition, the ability of splenic macrophages to kill target Escherichia coli is significantly increased by exposure to the stressor [4].…”