Atopic Dermatitis (AD), also known as atopic eczema, is a chronic, persistent, and recurrent inflammatory skin disorder characterized by intense itching. AD is the leading non-fatal skin condition in terms of disease burden. Its multifactorial etiology includes genetic predisposition, immune dysfunction, epidermal barrier defects, and environmental factors. Clinically, AD presents as persistent itching, erythema, cracking, and/or dryness. It predominantly affects children in urban and developed regions, with a prevalence of 20% in children and 10% in adults in developed countries over the past three decades.
1 Pathogenesis
The pathogenesis of AD involves epidermal barrier dysfunction, dysbiosis of the skin microbiome, and inflammation. Epidermal barrier disruption, often the initial step in AD development, can result from allergens, irritants, scratching, or FLG gene mutations. Dysbiosis, including colonization or infection by Staphylococcus aureus or Malassezia, further impairs the barrier, triggering inflammatory responses, particularly involving Th2-type inflammatory cells.
Keratinocyte-derived interleukins IL-33 and thymic stromal lymphopoietin (TSLP) recruit and activate type 2 inflammatory cells. Subsequent release of cytokines like IL-4, IL-13, and IL-31 exacerbates barrier dysfunction, promotes itching, and perpetuates dysbiosis. Th22-mediated inflammation, driven by IL-22, contributes to abnormal keratinocyte differentiation and epithelial hyperplasia. Additional mediators, including IL-5, IL-17, IL-12, and IL-23, are also implicated.
Advances in understanding AD pathogenesis have led to the development of innovative therapeutic targets. For instance, Dupilumab, a fully human monoclonal antibody, inhibits IL-4 and IL-13 signaling by binding specifically to the IL-4Rα subunit of their shared receptor complex. Tralokinumab (anti-IL-13), approved by the FDA and in the EU, selectively inhibits IL-13. Additionally, JAK inhibitors like Baricitinib, Upadacitinib, and Abrocitinib have been employed in AD treatment. Emerging therapies target OX40, TSLP, IL-22, IL-33, IL-31, IL-12/23, IL-17, IgE, and IL-5.
2 Construction of Animal Models
Animal models are invaluable for exploring disease mechanisms and developing new therapeutic strategies. A variety of AD models have been established using animals such as rabbits, rats, mice, guinea pigs, and dogs. Mice are particularly favored due to their cost-effectiveness, ease of model establishment, and suitability for genetic manipulation.
Based on induction methods, AD models can be categorized as:
- Spontaneous models: High fidelity but costly.
- Induced models: Cost-effective and widely used for studying pathophysiology and drug screening.
- Genetic models: High reproducibility but resource-intensive.
Among induced models, sensitizers such as OVA (ovalbumin), DNCB (2,4-dinitrochlorobenzene), DNFB (2,4-dinitrofluorobenzene), and Staphylococcus aureus superantigens are commonly used. Below are examples of model construction:
- OVA-induced AD model: Mice receive intraperitoneal injections of 10 µg OVA and 4 mg aluminum hydroxide (200 µL) on days 0, 7, and 14. After depilation, OVA-soaked patches (1 cm²) are applied to the dorsal skin for seven days, replaced daily, and repeated after a one-week interval.
- DNCB-induced AD model: Depilated dorsal skin is sensitized with 200 µL of 1% DNCB solution on day After two weeks, 200 µL of 0.2% DNCB is applied twice weekly for four weeks.
3 Evaluation of Model Effectiveness
3.1 Clinical Scoring
Clinical observation of skin lesions, including erythema/hemorrhage, edema/papules, excoriation/erosion, and scaling/dryness, is scored from 0 (none) to 3 (severe). Total scores range from 0 to 12, adapted from the Eczema Area and Severity Index (EASI).
3.2 Ear Thickness
For ear models, ear thickness measurements serve as an indicator of inflammation, complementing clinical scores for edema/papules.
3.3 Scratching Behavior
Scratching frequency at affected sites (ears or dorsum) is a supplementary evaluation metric.
3.4 Histopathology
Histological analysis reveals pathological changes such as hyperkeratosis, scab formation, ulcers/erosions, epidermal hyperplasia, dermal inflammatory infiltrates, and vascular congestion. Toluidine blue staining is used to quantify mast cells, characterized by ovoid shapes and densely packed granules.
3.5 Biomarker Analysis
Biomarker evaluation includes elevated serum IgE levels and cytokines such as IL-4, IL-5, and IFN-γ.
4 Summary and Outlook
AD is a significant public health challenge with a complex pathogenesis. Despite substantial progress in recent years, unresolved questions remain. Advances in scientific understanding and modeling techniques promise the development of animal models that better mimic human AD, facilitating research into pathogenesis and the evaluation of novel therapeutic targets.
