Introduction: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model. Methods: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue – a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined. Results: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom. Conclusion: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.

Urticaria, a skin allergy causing itchy bumps, is often treated with antihistamines. However, these treatments may not always be effective. To address this, researchers aim to develop new anti-allergic drugs. While several methods to induce urticaria-like symptoms in experimental animals have been explored, few are currently available. In a previous study, we successfully induced anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS) in hairless mice, resembling human urticaria. In this study, we investigated and clarified several key aspects using this method. First, we found that ASDIS in mice is mediated by an increase in vascular permeability, similar to human urticaria. This discovery supports the idea of considering mouse ASDIS as a model for human urticaria. Second, we demonstrated that ASDIS could be induced by IgE but not by histamine, a key mediator of vascular permeability increase. The unique plasma leakage induced by IgE was identified as a contributing factor to the urticaria-like symptoms in ASDIS. Third, a comparison of ASDIS and histamine-induced anaphylaxis in haired and hairless mice revealed that hairless mice were more sensitive. This suggests that hairless mice possess a unique mechanism induced by IgE, partially associated with histamine function. Finally, the inhibition of ASDIS by applying an adrenaline α1 receptor agonist to the skin strongly suggested the potential of this drug as an anti-allergic ointment. In summary, our mouse ASDIS model can be utilized as an urticaria model. Further detailed clarification of the underlying mechanisms of ASDIS induction will expedite the development of new anti-allergic drugs.

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