Gene expression analyses of murine skin highlight strain-dependent effects of Imiquimod on psoriatic signatures

There is currently no gold standard for an in vivo model of human psoriasis. However, the imiquimod (IMQ)-induced psoriasis model has come close to providing this due to its convenience and ability to elicit dermatitis that has some aspects of human plaque psoriasis.

Specifically, similar to human psoriasis, application of IMQ elicits skin erythema, scaling, keratinocye proliferation and dermal infiltration of pathogenic cells such as Th17 cells, which are an important target for the treatment of psoriasis.

Most commonly, female BALB/c mice are used as recipients of IMQ for pre-clinical testing. In this study, the investigators used RNA-seq to investigate psoriasis-associated signatures in male and female mice from seven laboratory strains: C57Bl/6 J, BALB.c J, CD1, DBA/1J, FVB/NJ, 129X1/SvJ, and MOLF/EiJ. In addition to RNA-seq, mice were compared based on their weight loss, skin changes, and spleen weight.

Male and female differences between each strain were less prominent than strain-dependent variability. RNA-seq analysis revealed that in most strains, IMQ induced a gene signature that corresponds to innate immune activation; a characteristic of human psoriasis. Amongst the two popular lab strains, the C57Bl/6 strain showed increased expression of genes associated with DNA replication and the IL-17/Th17 pathway, when compared to BALB/c mice.

MOLF/EiJ mice are a ‘wild derivative’ which have a unique genome which is divergent from the classic inbred strains. Application of IMQ to MOLF mice resulted in early mortality which is the result of aberrant epidermal responses, suggesting defective keratinocyte differentiation and barrier formation in these mice. Type 1 interferon responses which are strongly associated with human psoriasis were uniquely upregulated by IMQ in MOLF mice.

Whilst IMQ induced the expression of genes associated with psoriasis in most strains, the most common changes were associated with genes that are upregulated in other skin conditions such as wounds and infections, rather than psoriasis. This was observed in BLAB/c, 129/SvJ, DBA/1 and MOLF mice.

This is an informative manuscript that highlights the importance of choosing the appropriate strain of mouse, rather than disease trigger, as a pre-clinical tool. In this study, the effect of IMQ on the different strains was assessed, and RNA-seq analyses showed some significant changes, particularly with factors that are closely associated with the human condition, such as the Th17 and type 1 interferon pathways.

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Epistem's Models

At Epistem, we currently offer validated models in different strains to address skin changes and immune function associated with the application of 5% Imiquimod.

Our gene expression analysis and detailed protein analyses by flow cytometry and Luminex® can further assess disease pathogenesis by the identification of key molecules, or the intracellular mediators they express (cytokines, transcription factors).

Swindell et al. (2017). Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis.

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