A new study published in the Journal of Allergy and Clinical Immunology has uncovered the cellular and molecular mechanisms through which psychological stress worsens immunoglobulin E cutaneous allergic inflammation (IgE-CAI). The findings offer important insights into how stress contributes to the aggravation of allergic skin conditions like atopic dermatitis (AD), and could inform future treatments for stress-related inflammatory diseases.
The Role of Stress in Immune Responses
Psychological stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which trigger the release of key stress hormones, including epinephrine, norepinephrine, and glucocorticoids (GCs). These hormones, which regulate heart rate and blood pressure, also interact with immune cells that express receptors for these molecules. Previous research has shown that fluctuations in these hormones can significantly impact immune responses.
Both glucocorticoids and catecholamines, the stress hormones, are known to suppress the TH1 immune response, which leads to altered immune cell dynamics. This stress-induced immune suppression has been linked to an increased risk of conditions like cancer and infections. In allergic conditions like atopic dermatitis, stress has been shown to exacerbate symptoms by increasing serum levels of allergen-specific IgE and promoting the infiltration of eosinophils into affected tissues.
Investigating the Impact of Stress on Allergic Skin Inflammation
The current study aimed to explore the molecular mechanisms behind stress-induced IgE-CAI. Using a restraint stress (RS) mouse model, the researchers evaluated how psychological stress influences allergic skin inflammation. In this model, mice were restrained for two hours each day for seven days, with IgE-CAI induced on the final day through the administration of anti-2,4,6-trinitrophenol (TNP)-IgE and an antigen challenge.
The study also controlled for intestinal flora development by housing the RS and unrestrained control (US) mice together, ensuring that differences in immune activation were due to the stress exposure itself. Mice in the RS group were separated during restraint periods to prevent stress in the control group.
Key Findings of the Study
The study found that ear swelling, a marker of IgE-CAI development, was significantly lower in RS mice compared to their unrestrained counterparts. A marked increase in serum corticosterone levels was noted immediately after restraint, though these levels returned to normal three days after the final restraint exposure.
Further experiments showed that exogenous administration of corticosterone reduced IgE-CAI development, suggesting a complex interaction between stress hormones and allergic inflammation. Histological analyses revealed increased cellular infiltration into skin lesions associated with IgE-CAI in RS mice, indicating that stress exacerbates allergic skin inflammation.
Fluorescence-activated cell sorting (FACS) analysis confirmed a two- to four-fold increase in eosinophils in the skin lesions of RS mice, compared to the US group. However, other immune cell types, including neutrophils, basophils, and PD-L2+ monocytes/macrophages, did not show significant differences between the groups, further highlighting the pivotal role of eosinophils in stress-induced IgE-CAI exacerbation.
Role of Sympathetic Nervous System and Norepinephrine
To explore the role of the SNS in this process, the researchers conducted a systemic sympathetic denervation experiment using 6-hydroxydopamine (6-OHDA) treatment. They found that while stress exacerbated IgE-CAI in adrenalectomized mice, it had no effect in mice with sympathetic denervation. This suggests that norepinephrine released from sympathetic nerves, rather than from adrenal glands, plays a critical role in stress-induced IgE-CAI exacerbation.
The β2-adrenergic receptor (Adrb2), a receptor for norepinephrine, was identified as a key player in this process. In Adrb2 knockout mice, stress failed to induce an increase in IgE-CAI, highlighting the importance of the Adrb2 pathway in mediating the effects of stress on allergic inflammation.
Mechanisms of Exacerbation
The study further examined how stress-induced immune changes contribute to inflammation. Stress led to an increase in sympathetic nerve activity and norepinephrine secretion from the rostral medullary raphe region (rMR), which exacerbates IgE-CAI. Norepinephrine from sympathetic nerves acted on Adrb2 receptors on monocytes and PD-L2+ macrophages, impairing their anti-inflammatory functions.
RNA sequencing revealed reduced expression of efferocytosis-related genes, including Gas6 and MerTK, in RS mice. This reduction in efferocytosis, the process by which immune cells clear dead cells, leads to the accumulation of dead cells in inflamed tissues. These dead cells release damage-associated molecular patterns (DAMPs), which trigger the induction of CCL24, a chemokine that recruits eosinophils to the site of inflammation, further exacerbating IgE-CAI.
Conclusion and Implications
The study concludes that psychological stress exacerbates IgE-CAI through a sympathetic nervous system- and β2-adrenergic receptor-dependent mechanism. Stress impairs the anti-inflammatory actions of PD-L2+ macrophages, leading to increased inflammation. These findings suggest that enhancing the efferocytosis capacity of macrophages could be a promising therapeutic strategy for treating stress-aggravated inflammatory diseases like atopic dermatitis.
This research provides new insights into how psychological stress influences allergic skin inflammation at the molecular level and opens the door to potential treatments targeting the immune system’s response to stress.
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