The Role of Epithelial Barriers in Type 2 Inflammation

The Role of Epithelial Barriers in Type 2 Inflammation

Epithelial barriers serve as the first line of defense against environmental insults, including allergens and pathogens. In individuals suffering from conditions characterized by type 2 inflammation, such as asthma, atopic dermatitis, and eosinophilic esophagitis, the integrity of these epithelial barriers is often compromised. This dysfunction is pivotal in the pathogenesis of various type 2 inflammatory diseases, as it promotes an exaggerated immune response mediated by type 2 cytokines.

Recent research highlights that epithelial cells, when exposed to allergens, release alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). These alarmins activate type 2 immune pathways, promoting the recruitment of immune cells like eosinophils and mast cells, which exacerbate inflammation (Meng et al., 2025). The role of tight junctions in maintaining barrier integrity is also critical, as disruptions in these structures facilitate the penetration of allergens, leading to enhanced immune activation (Meng et al., 2025).

Figure 1: Structure of Epithelial Tight Junctions

The dysfunction of these barriers can lead to a cascade of events that perpetuate inflammation and allergic responses. For example, in asthma, epithelial cells’ exposure to allergens results in increased permeability, which is mediated by cytokines such as IL-4 and IL-13. These cytokines not only exacerbate inflammation but also lead to structural changes in the airway epithelium, promoting chronic symptoms (Meng et al., 2025).

Key Cytokines Driving Type 2 Immune Responses

Cytokines play a pivotal role in orchestrating the immune response associated with type 2 inflammation. The primary cytokines involved include IL-4, IL-5, and IL-13, which are produced by Th2 cells and group 2 innate lymphoid cells (ILC2s). These cytokines are central to the pathophysiology of various allergic conditions.

• IL-4: This cytokine is crucial for B cell differentiation and the production of IgE antibodies. It also promotes the expression of adhesion molecules on endothelial cells, facilitating the recruitment of eosinophils (Meng et al., 2025).
• IL-5: Specifically involved in the growth and activation of eosinophils, IL-5 is essential for the accumulation of these cells in tissues during allergic inflammation (Meng et al., 2025).
• IL-13: Similar to IL-4, IL-13 enhances IgE production, promotes mucus hypersecretion, and contributes to the remodeling of airway tissues by stimulating fibroblast activity (Meng et al., 2025).

These cytokines not only perpetuate the inflammatory response but also contribute to systemic effects observed in patients suffering from type 2 inflammatory diseases. Understanding the regulatory mechanisms of these cytokines is crucial for developing targeted therapies aimed at mitigating their effects.

Table 1: Role of Key Cytokines in Type 2 Inflammation

Common Conditions Associated with Type 2 Inflammation

Type 2 inflammation is associated with a variety of chronic conditions, each characterized by similar immunological profiles but affecting different organ systems. These include:

1. Asthma: One of the most prevalent conditions associated with type 2 inflammation, asthma is characterized by airway hyperresponsiveness, bronchial obstruction, and inflammation. The presence of elevated eosinophils and IgE levels is often observed in asthma patients (Meng et al., 2025).

2. Atopic Dermatitis (AD): This chronic skin condition results in dry, itchy skin and eczematous lesions. It is often exacerbated by environmental allergens and is marked by barrier dysfunction and increased sensitivity to allergens (Meng et al., 2025).

3. Chronic Rhinosinusitis with Nasal Polyps (CRSwNP): This condition involves inflammation of the nasal and sinus mucosa, leading to polyp formation. Patients typically exhibit high levels of eosinophils and Th2 cytokines in nasal tissues (Meng et al., 2025).

4. Eosinophilic Esophagitis (EoE): A chronic immune-mediated condition, EoE is characterized by eosinophilic infiltration of the esophagus, leading to symptoms like dysphagia and food impaction. This condition has been linked to food allergens and environmental triggers (Meng et al., 2025).

These conditions often coexist, complicating diagnosis and treatment. The shared pathophysiological mechanisms highlight the importance of a comprehensive approach to managing type 2 inflammation across different diseases.

Innovative Therapies Targeting Epithelial Barrier Dysfunction

Recent advancements in the treatment of type 2 inflammatory diseases have focused on restoring epithelial barrier function and inhibiting key cytokines involved in the inflammatory response. Innovative therapies include:

• Biologics: Targeted therapies such as monoclonal antibodies against IL-4, IL-5, and IL-13 have shown promise in reducing inflammation and improving symptoms in conditions like asthma and AD. For instance, dupilumab, an IL-4Rα blocker, has been approved for use in multiple allergic conditions, demonstrating efficacy in reducing exacerbations and improving quality of life (Meng et al., 2025).

• Barrier Restorative Therapies: These therapies aim to enhance the integrity of epithelial barriers. Agents that promote the expression of tight junction proteins or inhibit the activity of inflammatory cytokines are being investigated. For example, JAK inhibitors like tofacitinib have demonstrated potential in restoring barrier function in patients with AD by modulating the immune response and promoting keratinocyte differentiation (Meng et al., 2025).

• Nutritional Interventions: Emerging evidence suggests that certain dietary components may support epithelial health. For instance, omega-3 fatty acids and probiotics have been studied for their potential to modulate immune responses and enhance barrier function (Meng et al., 2025).

The development of such therapies underscores the need for individualized treatment strategies that address the underlying mechanisms of type 2 inflammation.

The Impact of Environmental Factors on Barrier Integrity

Environmental factors play a significant role in the maintenance of epithelial barrier integrity. Exposure to pollutants, allergens, and other environmental toxins can exacerbate barrier dysfunction, leading to increased susceptibility to type 2 inflammatory diseases.

• Air Pollution: Studies have shown that exposure to fine particulate matter (PM2.5) is associated with increased skin redness and inflammatory responses. Air pollutants can penetrate epithelial barriers and disrupt their function, leading to inflammation and exacerbating conditions like asthma and AD (Chan et al., 2025).

• Allergen Exposure: Continuous exposure to environmental allergens, such as pollen and dust mites, can lead to persistent inflammation and exacerbate symptoms in sensitized individuals. The interaction between allergens and the immune system is a critical factor in the pathogenesis of type 2 inflammatory diseases (Meng et al., 2025).

• Lifestyle Factors: Diet, physical activity, and stress levels can also influence immune responses and epithelial barrier function. For example, a diet high in processed foods may negatively impact gut microbiota composition and, consequently, epithelial integrity (Meng et al., 2025).

Understanding the interplay between environmental factors and epithelial barrier integrity is essential for developing effective prevention and treatment strategies for type 2 inflammation-related conditions.

FAQ

What is type 2 inflammation?

Type 2 inflammation is an immune response characterized by the activation of Th2 cells and the production of cytokines such as IL-4, IL-5, and IL-13, leading to allergic reactions and inflammation in various tissues.

What conditions are associated with type 2 inflammation?

Common conditions include asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis.

How do cytokines contribute to type 2 inflammation?

Cytokines like IL-4 and IL-13 promote the recruitment of immune cells, enhance IgE production, and disrupt epithelial barrier function, perpetuating the inflammatory response.

What therapies are available for managing type 2 inflammation?

Innovative therapies include biologics targeting specific cytokines, barrier restorative therapies, and nutritional interventions aimed at supporting epithelial health.

How do environmental factors affect type 2 inflammation?

Environmental factors such as air pollution and allergen exposure can exacerbate epithelial barrier dysfunction, leading to increased inflammation and worsening of associated conditions.

References

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