Social stress and asthma: the role of corticosteroid insensitivity

Abstract

Psychosocial stress alters susceptibility to infectious and systemic illnesses and may enhance airway inflammation in asthma by modulating immune cell function through neural and hormonal pathways. Stress activates the hypothalamic-pituitary-adrenal axis. Release of endogenous glucocorticoids, as a consequence, may play a prominent role in altering the airway immune homeostasis. Despite substantial corticosteroid and catecholamine plasma levels, chronic psychosocial stress evokes asthma exacerbations. Animal studies suggest that social stress induces corticosteroid insensitivity that in part may be a result of impaired glucocorticoid receptor expression and/or function. Such mechanisms likely promote and amplify airway inflammation in response to infections, allergen, or irritant exposure. This review discusses evidence of an altered corticosteroid responsive state as a consequence of chronic psychosocial stress. Elucidation of the mechanisms of stress-induced impairment of glucocorticoid responsiveness and immune homeostasis may identify novel therapeutic targets that could improve asthma management.

Figure 1

Mechanisms of glucocorticoid action. The activated glucocorticoid receptor (GR) homodimer binds to glucocorticoid response elements (GRE), located within regulatory regions of glucocorticoid-responsive genes in the nucleus. (A): Positive GRE mediates transcriptional up-regulation of anti-inflammatory genes such as IκBα, the glucocorticoid-inducible leucine zipper (GILZ) or IL-10. B: Negative GRE mediates transcriptional down-regulation. C-D: In monomeric form the activated GR may interact with other transcription factors such as nuclear factor κB (NFκB). (C): This interaction can occur indirectly through transcriptional co-factor (HDAC) binding or (D): by RNA polymerase dephosphorylation.

Figure 2

Hypothesized mechanisms by which glucocorticoid resistance could occur. (A): Glucocorticoid binding to the GR induces molecular rearrangement of the GR-HSP90 heterocomplex and promotes GR nuclear translocation, homodimerization, and DNA-binding. (B): This process can be modulated by GR/NF-κB interactions, directly by affecting transactivation (GRE-mediated) as well as transrepression of GR functions. Indirect inhibition of the GR function maybe achieved by transcription factor “tethering”.

Figure 3

Proposed mechanism of how stress-induced glucocorticoid insensitivity could affect the innate immune system during the allergic airway response. (A): Altered corticosteroid responsiveness of airway epithelial cells may inhibit SP-D production. (B): Stress abrogates corticosteroid responsiveness of proinflammatory dendritic cells. (C): Diminished SP-D levels will result in a failure to protect against dendritic cell and Th2-cell activation and the consequent allergic airway response.