Construction of a chronic spontaneous urticaria–relevant IgE-mediated mouse model based on passive cutaneous anaphylaxis and its transcriptome analysis

Abstract

Background

Chronic spontaneous urticaria (CSU) is a common immune-related skin disorder with an unclear pathogenesis and no universally accepted animal model. The passive cutaneous anaphylaxis (PCA) model is the commonly used model in CSU research.

Methods

To propose a modification to the PCA model to improve its alignment with CSU, we established a recurrent PCA (Re-PCA) model via 6 repeated injections of 2,4-dinitrophenyl–human serum albumin (DNP-HSA)-specific IgE and DNP-HSA and compared it to the PCA model. We assessed vascular permeability, scratch frequency scoring, histologic staining, flow cytometry, reverse transcription PCR, enzyme-linked immunosorbent assay, and RNA sequencing to compare phenotypic differences.

Results

The Re-PCA model exhibited more stable and significant skin changes associated with chronic urticaria compared to the PCA model. Lesional tissues of Re-PCA mice showed significantly increased degranulated mast cells and increased immune cell infiltration. Compared to the PCA group, peripheral blood histamine and tryptase levels of Re-PCA mice were significantly elevated. The utilization of histamine receptor blocker, c-Kit- and BTK-targeting drugs abrogated the phenotype of PCA and Re-PCA models. The gene expression profile of the Re-PCA lesions revealed enrichment of more genes and signaling pathways associated with CSU.

Conclusions

Our recurrent IgE-mediated mouse model exhibited greater immunologic and transcriptional relevance to CSU than the commonly used PCA model, which will facilitate research into the pathogenesis of CSU and advance our understanding of its underlying mechanisms.