Abstract
BackgroundImiquimod (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.MethodsRNA-seq was used to evaluate the psoriasiform phenotype elicited by 6 days of Aldara (5% IMQ) treatment in both sexes of seven mouse strains (C57BL/6 J (B6), BALB/cJ, CD1, DBA/1 J, FVB/NJ, 129X1/SvJ, and MOLF/EiJ).ResultsIn 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 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 B6). Compared with BALB/c, the B6 phenotype showed increased expression of genes associated with DNA replication, IL-17A stimulation, and activated CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Although IMQ-induced expression shifts mirrored psoriasis, responses in BALB/c, 129/SvJ, DBA, and MOLF mice were more consistent with other human skin conditions (e.g., wounds or infections). IMQ responses in B6 mice were most consistent with human psoriasis and best replicated expression patterns specific to psoriasis lesions.ConclusionsThese findings demonstrate strain-dependent aspects of IMQ dermatitis in mice. We have shown that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. Nonetheless, our findings suggest that B6 mice provide a better background than other strains for modeling psoriasis disease mechanisms.
Highlights
Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis
Anti-viral and mitotic pathways activated in psoriasis lesions have strain-dependent responses to IMQ in mice We identified Gene Ontology (GO) biological process (BP) terms significantly overrepresented among genes with elevated expression in psoriasis lesions and evaluated whether corresponding mouse genes were altered by IMQ (Fig. 4a)
Using RNA-seq, we showed that strain and sex influence correspondence between Aldara (5% IMQ)induced dermatitis and human psoriasis, suggesting that phenotypes developing on alternative backgrounds model the human disease to differing extents
Summary
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. Swindell et al Genome Medicine (2017) 9:24 cytokines, and the presence of T lymphocytes [3, 5, 6]. All of these features are consistent with human psoriasis lesions and accepted models of cutaneous lesion development [1, 2]. IMQ has been viewed as a convenient and easy-to-use mouse model of acute inflammatory response, which has been applied to facilitate mechanistic studies that would otherwise prove difficult or impossible to perform in humans
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