title: Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis.
abstract: 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.
  
  
  
  RNA-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).
  
  
  
  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 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.
  
  
  
  These 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.
authors.affiliation: Ohio University, Heritage College of Osteopathic Medicine, Athens, OH, 45701-2979, USA. ws277814@ohio.edu.|Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA. ws277814@ohio.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
authors.forename: Kellie A
authors.initials: KA
authors.lastname: Michaels
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sutter
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
authors.forename: Doina
authors.initials: D
authors.lastname: Diaconu
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Sarkar
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Department of Dermatology, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.|The Murdough Family Center for Psoriasis, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000077271:Imiquimod; D020381:Interleukin-17 / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012737:Sex Factors; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000634:Aminoquinolines; D020381:Interleukin-17; D000077271:Imiquimod
keywords: Aldara; Differentiation; Epidermis; IL-17A; Interferon; Keratinocyte; RNA-seq; Toll-like receptor