In a recent study, researchers explored how psychological stress can worsen skin allergies like eczema, hives, and contact dermatitis. Psychological stress is increasingly recognized as a key factor in the exacerbation of various allergic conditions, yet the precise cellular and molecular mechanisms by which it influences allergic inflammation remain poorly understood.
The study sheds light on the role of the sympathetic nervous system and specific immune cells in this process, offering new insights into potential therapeutic targets for stress-aggravated allergic conditions.
Can Stress Worsen Skin Allergies?
The study’s primary objective was to determine how psychological stress worsens skin allergies or IgE-mediated cutaneous allergic inflammation (IgE-CAI). IgE-CAI is a complex inflammatory response involving various immune cells, including basophils and eosinophils.
Its resolution depends on the anti-inflammatory functions of programmed death ligand 2 (PD-L2)-positive macrophages. However, the study found that psychological stress diminishes the anti-inflammatory capacity of these macrophages, thereby prolonging and intensifying the inflammatory response.
To identify the neural pathways involved in this stress-induced exacerbation, the researchers conducted denervation and brain destruction experiments in mice. These experiments revealed that the sympathetic nervous system, particularly through the activation of β2-adrenergic receptors (Adrb2), plays a crucial role in this process. This finding suggests that the body’s stress response, mediated by the sympathetic nervous system, directly influences immune function in allergic inflammation.
Stress can change your bodily response to stress
The study’s next step was to investigate how stress alters the function of PD-L2-positive macrophages, which are key players in resolving inflammation. The researchers used advanced techniques to show that psychological stress weakens the anti-inflammatory role of specific macrophages by activating Adrb2.
Stressed macrophages had lower levels of key genes like Gas6 and MerTK, which are essential for clearing dead cells from tissues (efferocytosis). As a result, these macrophages became less effective at removing dead cells from IgE-CAI lesions, worsening the inflammation.
The impaired efferocytic capacity of these macrophages had significant consequences for the inflammatory response. The accumulation of dead cells in the skin lesions created a pro-inflammatory environment that promoted further eosinophil infiltration.
Eosinophils are a type of immune cell associated with allergic inflammation and tissue damage. The researchers found that the increased eosinophil infiltration was driven by the production of CCL24, a chemokine that attracts eosinophils to sites of inflammation. Importantly, this process was found to be Caspase-1-dependent. Caspase-1 is an enzyme involved in the inflammatory response, particularly in activating inflammatory cytokines.
Highlights of the study
The researchers demonstrated that inhibiting Caspase-1 reduced both the production of CCL24 and the exacerbation of IgE-CAI in stressed mice. This finding highlights the potential of targeting the Caspase-1 pathway as a therapeutic strategy for stress-aggravated allergic conditions. By preventing the Caspase-1-dependent production of CCL24, it may be possible to reduce eosinophil infiltration and alleviate the severity of allergic inflammation.
One of the study’s most significant findings is the identification of the link between psychological stress and the diminished anti-inflammatory capacity of PD-L2-positive macrophages. PD-L2-positive macrophages play a crucial role in resolving inflammation by clearing dead cells and producing anti-inflammatory molecules. However, the activation of Adrb2 by stress-related neurotransmitters impairs their efferocytic function, leading to the accumulation of dead cells and a prolonged inflammatory response.
This study also provides important insights into the molecular mechanisms underlying the impaired efferocytic capacity of stressed macrophages. RNA sequencing analysis revealed that stressed PD-L2-positive macrophages exhibit decreased expression of key efferocytosis-related genes, including Gas6 and MerTK.
Gas6 is a protein that bridges dead cells to macrophages, facilitating their clearance, while MerTK is a receptor that plays a critical role in recognizing and engulfing dead cells. The reduced expression of these genes in stressed macrophages explains their diminished ability to clear dead cells from inflamed tissues.
The findings of this study have significant implications for understanding how psychological stress influences allergic inflammation. They highlight the importance of the sympathetic nervous system and the β2-adrenergic receptor pathway in mediating the effects of stress on immune function. By identifying the specific immune cells and molecular pathways involved in stress-aggravated allergic inflammation, the study opens new avenues for therapeutic intervention.
Targeting the β2-adrenergic receptor pathway or enhancing the efferocytic capacity of PD-L2-positive macrophages could offer promising strategies for treating stress-exacerbated allergic conditions. For example, drugs that inhibit Adrb2 activation or boost the expression of efferocytosis-related genes like Gas6 and MerTK may help restore the anti-inflammatory functions of PD-L2-positive macrophages and reduce the severity of allergic inflammation.
Takeaway
This study provides compelling evidence that psychological stress exacerbates IgE-mediated cutaneous allergic inflammation by impairing the anti-inflammatory functions of PD-L2-positive macrophages. The activation of the β2-adrenergic receptor pathway diminishes the efferocytic capacity of these macrophages, leading to the accumulation of dead cells and increased eosinophil infiltration through Caspase-1-dependent production of CCL24. These findings offer valuable insights into the complex interplay between psychological stress and immune function, with potential implications for developing new treatments for stress-aggravated allergic conditions.
