Atopic dermatitis is a chronic inflammatory skin condition resulting in intensely itchy and eczematous skin. To understand this disease, scientists use mouse models to replicate aspects of the condition. This approach allows for a controlled examination of the genetic, immune, and environmental factors that contribute to atopic dermatitis and for testing potential treatments.
Methods for Inducing Atopic Dermatitis in Mice
Scientists employ several methods to create mouse models that mimic the signs of atopic dermatitis. One approach is chemical sensitization, where specific substances are applied to the mouse’s skin to provoke an immune reaction. For example, repeated application of a vitamin D3 analog known as MC903 can induce skin inflammation characterized by a specific type of immune response. Small molecule irritants called haptens, such as oxazolone, can also trigger an allergic reaction that becomes a chronic inflammation resembling the human condition.
Another technique involves genetic modification to probe the function of genes implicated in the human disease. A prominent example is the development of mice with a non-functional filaggrin (FLG) gene. Filaggrin is a protein that helps form the outer layer of the skin, and mutations in the FLG gene are a known risk factor for atopic dermatitis. By creating “knockout” mice that lack this gene, researchers can study how a compromised skin barrier directly contributes to disease development.
Some mouse strains naturally develop skin issues similar to atopic dermatitis without direct intervention. The NC/Nga mouse is a well-established example of such a spontaneous model. These mice develop skin lesions and elevated levels of Immunoglobulin E (IgE), an antibody associated with allergic reactions, only when housed in conventional, non-sterile environments. The symptoms do not appear in sterile conditions, which highlights how environmental triggers can initiate the disease in genetically predisposed individuals.
Uncovering Disease Mechanisms with Mouse Models
Mouse models have shaped our understanding of how atopic dermatitis begins and progresses, helping to support the “outside-in” hypothesis. This theory proposes that a defect in the skin’s barrier function is the initial event, which allows allergens and microbes to penetrate the skin and trigger an inflammatory immune response. Studies using mice with genetic defects in skin barrier proteins like filaggrin show that a weakened barrier precedes inflammation, providing strong evidence for this sequence.
These models have also enabled the identification of the immune cells and signaling molecules that drive inflammation and itch. Research points to the T helper 2 (Th2) lymphocyte as a central player. These cells produce cytokines, particularly Interleukin-4 (IL-4) and Interleukin-13 (IL-13), which orchestrate the inflammatory cascade.
These cytokines are responsible for many features of the disease. IL-4 and IL-13 can weaken the skin barrier by reducing the expression of proteins like filaggrin, creating a cycle of barrier dysfunction and inflammation. They also stimulate B cells to produce IgE antibodies and are involved in generating the sensation of itch. This molecular knowledge from mouse models has been used to develop targeted therapies for patients.
Assessing Disease Severity and Treatment Efficacy
To determine the effectiveness of potential treatments, researchers need reliable methods to measure disease severity in mouse models. A primary technique is a clinical scoring system, adapted from human assessment tools. Scientists visually inspect the affected skin and assign numerical scores based on the extent and intensity of signs like:
- Redness (erythema)
- Swelling (edema)
- Skin thickening
- Scratch marks (excoriation)
This provides a standardized, non-invasive way to track disease progression and response to therapy.
For a more detailed analysis, investigators perform histological examinations of skin tissue. This involves taking small skin samples, slicing them into thin sections, and staining them for viewing under a microscope. This microscopic view reveals changes like a thickened epidermis and the infiltration of inflammatory cells like eosinophils and mast cells. The degree of these cellular changes offers an in-depth measure of the underlying inflammation.
Quantitative data is also gathered by measuring specific biomarkers in the blood and skin. A common practice is to measure the levels of total and allergen-specific IgE antibodies in the serum. Researchers also quantify the concentration of inflammatory cytokines, like IL-4 and IL-13, in skin tissue or blood. These molecular measurements provide objective data on the immune system’s activity, complementing other assessments.
Translating Mouse Model Findings to Human Patients
While mouse models are valuable, it is important to recognize their limitations when translating findings to human health. No single model can perfectly replicate the complexity of human atopic dermatitis. There are biological differences between mouse and human skin; mouse skin is thinner, has a higher density of hair follicles, and a different composition of immune cells. These distinctions can influence how the skin reacts to irritants and absorbs topical medications, meaning results are not always directly transferable.
Despite these differences, mouse models are used in the preclinical phase of drug development. They provide a platform for the initial screening of new therapies for safety and effectiveness before they can be considered for human testing. This process allows researchers to test hypotheses and ensures that only the most promising treatments are advanced for evaluation in people, accelerating the development of new options for patients with atopic dermatitis.