Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

Background: Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. Whether this phenotype depends on strain or sex has never been systematically investigated on a large scale. Such effects, however, could lead to conflicts among studies, while further impacting study outcomes and efforts to translate research findings. Methods: RNA-seq was used to evaluate the psoriasiform phenotype elicited by IMQ in both sexes of 7 mouse strains (C57BL/6J, BALB/cJ, CD1, DBA/1J, FVB/NJ, 129X1/SvJ and MOLF/EiJ). Results: In most strains, IMQ altered gene expression in a manner consistent with human psoriasis, partly due to innate immune activation and decreased homeostatic gene expression. The IMQ response of MOLF males was aberrant, however, with decreased expression of differentiation-associated genes (elevated in other strains). Key aspects of the IMQ response differed between the two most commonly studied strains (BALB/c and C57BL/6). Compared with BALB/c, the C57BL/6 phenotype showed increased expression of genes associated with DNA replication, IL-17A activation and CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Surprisingly, although IMQ-induced expression shifts mirrored psoriasis, correspondence was similar or better for other human skin diseases (e.g., eschars, acne, atopic dermatitis). For BALB/c, MOLF, and 129X1 strains, genes altered by IMQ corresponded better to those altered in human skin infections or wounds compared with those altered in psoriasis lesions. Conclusions: These findings demonstrate strain-dependent aspects of IMQ dermatitis that warrant consideration in planning and interpreting experimental studies. We have further shown that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. These observations challenge the view of IMQ dermatitis as a mouse phenotype uniquely appropriate for studying psoriasis as opposed to other human skin conditions. Overall design: RNA-seq was used to investigate the psoriasiform phenotype that develops following topical IMQ treatment in male and female mice of 7 laboratory mouse strains (C57BL/6J, BALB/cJ, CD1, DBA/1J, FVB/NJ, 129X1/SvJ and MOLF/EiJ). Mouse back skin was treated with 62.5 mg AldaraTM (5% IMQ) or a non-toxic lanolin-derived occlusion cream (CTL) once per day for 5 consecutive days. Mice were sacrificed on day 6 and skin biopsies were collected. Overall, RNA-seq was used to profile transcriptomes of 56 CTL- and IMQ-treated skin samples (7 strains × 2 sexes × 2 treatments; n = 2 samples per strain/sex/treatment combination).

56

Swindell WR, Michaels KA, Sutter AJ, Diaconu D, Fritz Y, Xing X, Sarkar MK, Liang Y, Tsoi A, Gudjonsson JE, Ward NL