Animal models of psoriasis—highlights and drawbacks

Research into the pathophysiology of psoriasis remains challenging, because this disease does not occur naturally in laboratory animals. However, specific aspects of its complex immune-pathology can be illuminated through transgenic, knockout, xenotransplantation, immunological reconstitution, drug-induced, or spontaneous mutation models in rodents. Although some of these approaches have already been pursued for more than 5 decades and even more models have been described in recent times, they have surprisingly not yet been systematically validated. As a consequence, researchers regularly examine specific aspects that only partially reflect the complex overall picture of the human disease. Nonetheless, animal models are of great utility to investigate inflammatory mediators, the communication between cells of the innate and the adaptive immune systems, the role of resident cells as well as new therapies. Of note, various manipulations in experimental animals resulted in rather similar phenotypes. These were called “psoriasiform”, “psoriasis-like” or even “psoriasis” usually on the basis of some similarities with the human disorder. Xenotransplantation of human skin onto immunocompromised animals can overcome this limitation only in part. In this review, we elucidate approaches for the generation of animal models of psoriasis and assess their strengths and limitations with a certain focus on more recently developed models. Research into the pathophysiology of psoriasis remains challenging, because this disease does not occur naturally in laboratory animals. However, specific aspects of its complex immune-pathology can be illuminated through transgenic, knockout, xenotransplantation, immunological reconstitution, drug-induced, or spontaneous mutation models in rodents. Although some of these approaches have already been pursued for more than 5 decades and even more models have been described in recent times, they have surprisingly not yet been systematically validated. As a consequence, researchers regularly examine specific aspects that only partially reflect the complex overall picture of the human disease. Nonetheless, animal models are of great utility to investigate inflammatory mediators, the communication between cells of the innate and the adaptive immune systems, the role of resident cells as well as new therapies. Of note, various manipulations in experimental animals resulted in rather similar phenotypes. These were called “psoriasiform”, “psoriasis-like” or even “psoriasis” usually on the basis of some similarities with the human disorder. Xenotransplantation of human skin onto immunocompromised animals can overcome this limitation only in part. In this review, we elucidate approaches for the generation of animal models of psoriasis and assess their strengths and limitations with a certain focus on more recently developed models. As a “model disease,” psoriasis has taught us much about fundamental processes in chronic inflammatory disorders and has contributed to the development of many highly effective modern therapies.1Boehncke W.H. Schön M.P. Psoriasis.Lancet. 2015; 386: 983-994Abstract Full Text Full Text PDF PubMed Scopus (875) Google Scholar, 2Schön M.P. Erpenbeck L. The interleukin-23/interleukin-17 axis links adaptive and innate immunity in psoriasis.Front Immunol. 2018; 9: 1323Crossref PubMed Scopus (72) Google Scholar, 3Conrad C. Gilliet M. Psoriasis: from pathogenesis to targeted therapies.Clin Rev Allergy Immunol. 2018; 54: 102-113Crossref PubMed Scopus (86) Google Scholar It is a systemic inflammatory disorder affecting primarily the skin and the joints, with a global prevalence of 2% to 3%.4Michalek I.M. Loring B. John S.M. A systematic review of worldwide epidemiology of psoriasis.J Eur Acad Dermatol Venereol. 2017; 31: 205-212Crossref PubMed Scopus (257) Google Scholar It has a well-established immunogenetic basis.5Bowcock A.M. Krueger J.G. Getting under the skin: the immunogenetics of psoriasis.Nat Rev Immunol. 2005; 5: 699-711Crossref PubMed Scopus (369) Google Scholar,6Harden J.L. Krueger J.G. Bowcock A.M. The immunogenetics of psoriasis: a comprehensive review.J Autoimmun. 2015; 64: 66-73Crossref PubMed Google Scholar Comorbid diseases include cardiovascular, metabolic, and mental disorders.7Boehncke W.H. Boehncke S. Schön M.P. Managing comorbid disease in patients with psoriasis.BMJ. 2010; 340: b5666Crossref PubMed Scopus (102) Google Scholar Psoriasis encompasses dysregulation and complex interactions of the innate and the adaptive immune systems as well as other components such as the epithelium, the vasculature and the cutaneous nervous system. There is accumulating evidence that both autoimmune and autoinflammatory mechanisms fuel the disease.8Schön M.P. Adaptive and innate immunity in psoriasis and other inflammatory disorders.Front Immunol. 2019; 10: 1764Crossref PubMed Scopus (32) Google Scholar As representatives of adaptive immunity, T cells play a pivotal part in psoriasis. Indeed, association of psoriasis with certain HLA alleles, the therapeutic success of T-cell–directed immunomodulation, the detection of putative autoantigens, or T-cell–centered animal models point to the prominent role of T cells in this disease. We know today that cluster of differentiation (CD)4+, IL-17–producing TH cells (TH17) are central protagonists in psoriasis.9Lauffer F, Eyerich K, Boehncke WH, Asadullah K, Beissert S, Ghoreschi K, et al. Cytokines of the IL-17 family in psoriasis. J Dtsch Dermatol Ges https://doi.org/10.1111/ddg.14124. Online ahead of print May 24, 2020.Google Scholar Release of IL-17 (most importantly IL-17A) triggers epidermal hyperplasia and contributes to immune cell activation, thus creating a vicious inflammatory circle. The discovery that other cells such as epidermal CD8+ T cells as well as cells of the innate immune response such as neutrophilic granulocytes, mast cells, and macrophages can also contain IL-17 has led to a paradigm shift and has catapulted the innate immune system back into the limelight of psoriasis research.10Schön M.P. Broekaert S.M. Erpenbeck L. Sexy again: the renaissance of neutrophils in psoriasis.Exp Dermatol. 2017; 26: 305-311Crossref PubMed Scopus (37) Google Scholar Innate lymphoid cell type 3 also produce IL-17A.11Villanova F. Flutter B. Tosi I. Grys K. Sreeneebus H. Perera G.K. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar Dysregulation of the IL-23/IL-17 cytokine axis, in particular in conjunction with TNF-α,12Chiricozzi A. Guttman-Yassky E. Suárez-Fariñas M. Nograles K.E. Tian S. Cardinale I. et al.Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.J Invest Dermatol. 2011; 131: 677-687Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar appears to lie at the heart of psoriasis and can trigger complex dysfunctions in almost all cutaneous (and, in part, systemic) cell types.13Blauvelt A. Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis.Clin Rev Allergy Immunol. 2018; 55: 379-390Crossref PubMed Scopus (122) Google Scholar For example, overstimulation of the IL-17 axis with the downstream cytokine IL-22 as well as other cytokines can trigger the production of numerous inflammatory mediators and chemoattractants as well as antimicrobial peptides secreted by keratinocytes. Some of these molecules may function as autoantigens, including double-stranded DNA or RNA (possibly derived from neutrophil extracellular traps [NETs]), cathelicidin (LL37 [37 amino acid cleavage product of cathelicidin]; alone or in complexes with RNA/DNA14Herster F. Bittner Z. Archer N.K. Dickhofer S. Eisel D. Eigenbrod T. et al.Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.Nat Commun. 2020; 11: 105Crossref PubMed Scopus (26) Google Scholar), or melanocytic A disintegrin and metalloproteinase with thrombospondin motif-like protein 5, thus fueling the global inflammatory response.15Arakawa A. Siewert K. Stöhr J. Besgen P. Kim S.M. Rühl G. et al.Melanocyte antigen triggers autoimmunity in human psoriasis.J Exp Med. 2015; 212: 2203-2212Crossref PubMed Scopus (165) Google Scholar,16Lande R. Botti E. Jandus C. Dojcinovic D. Fanelli G. Conrad C. et al.The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.Nat Commun. 2014; 5: 5621Crossref PubMed Scopus (255) Google Scholar Many insights into psoriasis—in particular into the efficacy of therapies and into complex interactions of immune cells and inflammatory mediators—come from animal models, especially in mice. In fact, the number of publications on animal models of psoriasis is steadily increasing (Fig 1). In this light, it is surprising that in the more than 5 decades in which animal models have been used for such investigations, no standardized experimental characterization of these models has yet taken place. Scientific interest in psoriasis remains very high, as exemplified by the large number of publications on its pathogenesis (more than 20,000 articles published since 1965, MEDLINE accessed March 5, 2020). Notwithstanding this ongoing extensive research, several central psoriasis-related questions still remain to be answered. The role of immunocyte subsets (eg, cells of the innate vs adaptive immune system) and the cross-talk between resident cutaneous cells and immigrating immune cells is not yet completely understood. Similarly, the (immuno)genetic basis of psoriasis, in spite of great advances during the last years that have seen the identification of several dozens of loci within the genome that are associated with psoriasis susceptibility, still warrants further research. Because basic and translational research on patients with psoriasis is often not possible due to ethical considerations and the very limited availability of human material, animal models are of great importance for the investigation of pathogenic mechanisms and therapeutic principles (Table I). However, mirroring the complex phenotype and pathophysiology of psoriasis in an animal model is challenging, if possible at all.17Gudjonsson J.E. Johnston A. Dyson M. Valdimarsson H. Elder J.T. Mouse models of psoriasis.J Invest Dermatol. 2007; 127: 1292-1308Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar,18Schön M.P. Animal models of psoriasis: a critical appraisal.Exp Dermatol. 2008; 17: 703-712Crossref PubMed Scopus (73) Google Scholar So how could such a psoriasis model generally be generated? There are at least 3 basic principles.Table ISelected rodent models with features of human psoriasisModelFeatures similar to psoriasis in skin compartmentsReferencesEpidermal changesVascular changesImmune cell changesSpontaneous mutations Ab miceMild acanthosis hyperkeratosisMild vasodilationSparse infiltrate, mast cell increase21Gates A.H. Karasek M. Hereditary absence of sebaceous glands in the mouse.Science. 1965; 148: 1471-1473Crossref PubMed Google Scholar,22Brown W.R. Hardy M.H. A hypothesis on the cause of chronic epidermal hyperproliferation in asebia mice.Clin Exp Dermatol. 1988; 13: 74-77Crossref PubMed Google Scholar Fsn miceAcanthosis, parakeratosisIncreased number and size of blood vesselsStrain-dependent neutrophil and T-lymphocyte infiltration, increased number of mast cells31Sundberg J.P. Dunstan R.W. Roop D.R. Beamer W.G. Full-thickness skin grafts from flaky skin mice to nude mice: maintenance of the psoriasiform phenotype.J Invest Dermatol. 1994; 102: 781-788Crossref PubMed Google Scholar,32Sundberg J.P. Beamer W.G. Shultz L.D. Dunstan R.W. Inherited mouse mutations as models of human adnexal, cornification, and papulosquamous dermatoses.J Invest Dermatol. 1990; 95: 62s-63sAbstract Full Text PDF PubMed Google Scholar Chronic proliferative dermatitis miceAcanthosis, parakeratosisIncreased dermal vascularityNeutrophils, lymphocytes28HogenEsch H. Gijbels M.J. Offerman E. van Hooft J. van Bekkum D.W. Zurcher C. A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice.Am J Pathol. 1993; 143: 972-982PubMed Google Scholar Flaky tail miceMild acanthosis and hyperkeratosisNot significantly alteredLymphocytes, eosinophils, macrophages25Presland R.B. Boggess D. Lewis S.P. Hull C. Fleckman P. Sundberg J.P. Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris.J Invest Dermatol. 2000; 115: 1072-1081Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 26Lane P.W. Two new mutations in linkage group XVI of the house mouse: flaky tail and varitint-waddler-J.J Hered. 1972; 63: 135-140Crossref PubMed Scopus (0) Google Scholar, 27Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (346) Google ScholarTransgenic rodents HLA-B27 transgenic ratsAcanthosis, hyperkeratosis, nail dystrophyHypervascularity, vasodilationMixed infiltrate containing lymphocytes and neutrophils64Hammer R.E. Maika S.D. Richardson J.A. Tang J.P. Taurog J.D. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders.Cell. 1990; 63: 1099-1112Abstract Full Text PDF PubMed Scopus (710) Google Scholar Suprabasal epidermal expression of α2, α5, or β1-integrin subunits in miceFocal parakeratosis, altered differentiation; induction of ICAM-1Increased vascularityNeutrophils, T lymphocytes59Carroll J.M. Romero M.R. Watt F.M. Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis.Cell. 1995; 83: 957-968Abstract Full Text PDF PubMed Scopus (0) Google Scholar Suprabasal epidermal expression of IFN-γ in miceParakeratosis, acanthosis, induction of ICAM-1 and MHC IIEnlarged dermal capillariesNeutrophils, T lymphocytes, macrophages in dermiş; loss of epidermal Langerhans cells48Carroll J.M. Crompton T. Seery J.P. Watt F.M. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss.J Invest Dermatol. 1997; 108: 412-422Abstract Full Text PDF PubMed Google Scholar Basal epidermal expression of IL-17A in miceHyper- and parakeratosis, induction of ICAM-1NDNeutrophils, macrophages, T lymphocytes105Croxford A.L. Karbach S. Kurschus F.C. Wortge S. Nikolaev A. Yogev N. et al.IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions.J Invest Dermatol. 2014; 134: 728-735Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Epidermal expression of Tie2 in miceHyper- and parakeratosisHypervascularity, vasodilation, angiogenesisT cells, dermal dendritic cells, macrophages54Wolfram J.A. Diaconu D. Hatala D.A. Rastegar J. Knutsen D.A. Lowther A. et al.Keratinocyte but not endothelial cell-specific overexpression of Tie2 leads to the development of psoriasis.Am J Pathol. 2009; 174: 1443-1458Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar CARD14-deficient miceAbrogation of skin inflammation induced by imiquimod or IL-23NDEssential role for several cell types of adaptive and innate immunity69Tanaka M. Kobiyama K. Honda T. Uchio-Yamada K. Natsume-Kitatani Y. Mizuguchi K. et al.Essential role of CARD14 in murine experimental psoriasis.J Immunol. 2018; 200: 71-81Crossref PubMed Scopus (18) Google Scholar,70Mellett M. Meier B. Mohanan D. Schairer R. Cheng P. Satoh T.K. et al.CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo.J Invest Dermatol. 2018; 138: 2010-2023Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar CD18 hypomorphic mice on PL/J genetic backgroundAcanthosis, hyperparakeratosis, altered differentiationIncreased vascularityMixed inflammatory infiltrate, microabscesses, pathogenic role of T cells and macrophages39Bullard D.C. Scharffetter-Kochanek K. McArthur M.J. Chosay J.G. McBride M.E. Montgomery C.A. et al.A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice.Proc Natl Acad Sci U S A. 1996; 93: 2116-2121Crossref PubMed Scopus (0) Google Scholar,67Wang H. Peters T. Kess D. Sindrilaru A. Oreshkova T. Van Rooijen N. et al.Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation.J Clin Invest. 2006; 116: 2105-2114Crossref PubMed Scopus (176) Google Scholar,68Kess D. Peters T. Zamek J. Wickenhauser C. Tawadros S. Loser K. et al.CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis.J Immunol. 2003; 171: 5697-5706Crossref PubMed Scopus (0) Google Scholar Epidermal overexpression of VEGF in miceNo overt changesHypervascularity and dilation of blood vessels, endothelial activationEnhanced leukocyte rolling, mast cell increase49Detmar M. Brown L.F. Schön M.P. Elicker B.M. Velasco P. Richard L. et al.Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice.J Invest Dermatol. 1998; 111: 1-6Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar Epidermal expression of latent human TGF-β1 in miceAcanthosis, hyperparakeratosis, altered keratinocyte differentiationIncreased vascularity, therapeutic effect of antiangiogenic treatmentİncreased number of T cells, neutrophils, mast cells51Li A.G. Wang D. Feng X.H. Wang X.J. Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder.Embo J. 2004; 23: 1770-1781Crossref PubMed Scopus (164) Google Scholar,62Zibert J.R. Wallbrecht K. Schön M. Mir L.M. Jacobsen G.K. Trochon-Joseph V. et al.Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions.J Clin Invest. 2011; 121: 410-421Crossref PubMed Scopus (28) Google Scholar İnducible epidermal deletion of JunB/c-Jun in miceAcanthosis, hyperkeratosisEnlarged blood vesselsİnflammatory infiltrate containing T cells, macrophages, neutrophils66Zenz R. Eferl R. Kenner L. Florin L. Hummerich L. Mehic D. et al.Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.Nature. 2005; 437: 369-375Crossref PubMed Scopus (447) Google Scholar Epidermal expression of BMP6 in miceEpidermal hyperplasia and hyperkeratosis in one line, opposite effects in another line with higher copy numbers of the transgeneNDİnflammatory infiltrate in dermiş and epidermis52Blessing M. Schirmacher P. Kaiser S. Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions.J Cell Biol. 1996; 135: 227-239Crossref PubMed Scopus (118) Google ScholarCRISPR/Cas9 genome editing N-WASP deficiency (N-WASP fl/fl K5 cre) plus keratinocyte-restricted IL-23A deletion in miceEpidermal hyperplasia in N-WASP–deficient mice alleviated by epidermal IL-23 deficiencyNDMast cells, granulocytes, and other mostly nonlymphoid cells74Li H. Yao Q. Mariscal A.G. Wu X. Hulse J. Pedersen E. et al.Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation.Nat Commun. 2018; 9: 1420Crossref PubMed Scopus (32) Google ScholarTopical modulation of skin environment Imiquimod-induced dermatitis in miceParakeratosis, hyperproliferation, induction of MHC IIIncreased vascularity, vasodilationNeutrophils, γδ T cells, dendritic cells, plasmacytoid dendritic cells, Langerhans cells82Hawkes J.E. Gudjonsson J.E. Ward N.L. The snowballing literature on imiquimod-induced skin inflammation in mice: a critical appraisal.J Invest Dermatol. 2017; 137: 546-549Abstract Full Text Full Text PDF PubMed Google Scholar,93van der Fits L. Mourits S. Voerman J.S. Kant M. Boon L. Laman J.D. et al.Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol. 2009; 182: 5836-5845Crossref PubMed Scopus (1026) Google Scholar,135Sumida H. Yanagida K. Kita Y. Abe J. Matsushima K. Nakamura M. et al.Interplay between CXCR2 and BLT1 facilitates neutrophil infiltration and resultant keratinocyte activation in a murine model of imiquimod-induced psoriasis.J Immunol. 2014; 192: 4361-4369Crossref PubMed Scopus (73) Google Scholar Dermal injection of IL-23 in miceParakeratosis, hyperproliferationProminent dermal blood vesselsNeutrophils, T cells, dendritic cells, macrophages40Chan J.R. Blumenschein W. Murphy E. Diveu C. Wiekowski M. Abbondanzo S. et al.IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.J Exp Med. 2006; 203: 2577-2587Crossref PubMed Scopus (501) Google Scholar IL-36 dependency in imiquimod-induced dermatitis in miceAcanthosis, hyperkeratosisIncreased vascularity, vasodilationNeutrophils, T cells, dendritic cells87Tortola L. Rosenwald E. Abel B. Blumberg H. Schäfer M. Coyle A.J. et al.Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk.J Clin Invest. 2012; 122: 3965-3976Crossref PubMed Scopus (258) Google ScholarT-cell transfer T-cell transfer from HLA-B27 transgenic rats into immunocompromised recipientsAcanthosis, hyperkeratosisNDMixed inflammatory infiltrate containing neutrophils, macrophages, lymphocytes65Breban M. Fernandez-Sueiro J.L. Richardson J.A. Hadavand R.R. Maika S.D. Hammer R.E. et al.T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats.J Immunol. 1996; 156: 794-803PubMed Google Scholar CD4+/CD45RBhi T-cell transfer into scid/scid miceParakeratosis, altered keratin expression, induction of ICAM-1, MHC II, and VEGFAngiogenesis, increased number and size of dermal blood vesselNeutrophils, T lymphocytes, mast cells38Schön M.P. Schön M. Warren H.B. Donohue J.P. Parker C.M. Cutaneous inflammatory disorder in integrin alphaE (CD103)-deficient mice.J Immunol. 2000; 165: 6583-6589Crossref PubMed Scopus (58) Google Scholar,75Schön M.P. Detmar M. Parker C.M. Murine psoriasis-like disorder induced by naive CD4+ T cells.Nat Med. 1997; 3: 183-188Crossref PubMed Scopus (137) Google Scholar,76Hong K. Chu A. Ludviksson B.R. Berg E.L. Ehrhardt R.O. IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder.J Immunol. 1999; 162: 7480-7491PubMed Google Scholar Dsg3H1-TH17 transfer into Rag2−/− miceParakeratosis, induction of MHC IINDTH1/17 cells, neutrophils, CD4+ Vβ6+ T cells79Nishimoto S. Kotani H. Tsuruta S. Shimizu N. Ito M. Shichita T. et al.Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation.J Immunol. 2013; 191: 3065-3072Crossref PubMed Scopus (31) Google ScholarXenotransplantation models Human tissue onto scid/scid miceHyperplasia, parakeratosis, induction of ICAM-1 and MHC IIPreserved hypervascularization in transplanted skin, murine blood vesselsNeutrophils, CD4+ T cells, CD8+ T cells148Wrone-Smith T. Nickoloff B.J. Dermal injection of immunocytes induces psoriasis.J Clin Invest. 1996; 98: 1878-1887Crossref PubMed Google Scholar,149Stenderup K. Rosada C. Worsaae A. Dagnaes-Hansen F. Steiniche T. Hasselager E. et al.Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model.Br J Dermatol. 2009; 160: 284-296Crossref PubMed Scopus (51) Google Scholar,158Boehncke W.H. The SCID-hu xenogeneic transplantation model: complex but telling.Arch Dermatol Res. 1999; 291: 367-373Crossref PubMed Scopus (0) Google Scholar,160Boehncke W.H. Dressel D. Zollner T.M. Kaufmann R. Pulling the trigger on psoriasis.Nature. 1996; 379: 777Crossref PubMed Google Scholar Human tissue onto nu/nu miceHyperplasia, parakeratosisPreserved hypervascularization in transplanted skinNeutrophils, T lymphocytes150Krueger G.G. Chambers D.A. Shelby J. Involved and uninvolved skin from psoriatic subjects: are they equally diseased? Assessment by skin transplanted to congenitally athymic (nude) mice.J Clin Invest. 1981; 68: 1548-1557Crossref PubMed Google Scholar, 151Fraki J.E. Briggaman R.A. Lazarus G.S. Uninvolved skin from psoriatic patients develops signs of involved psoriatic skin after being grafted onto nude mice.Science. 1982; 215: 685-687Crossref PubMed Google Scholar, 152Baker B.S. Brent L. Valdimarsson H. Powles A.V. al-Imara L. Walker M. et al.Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T-cell derived cytokines?.Br J Dermatol. 1992; 126: 105-110Crossref PubMed Google Scholar, 153Krueger G.G. Manning D.D. Malouf J. Ogden B. Long-term maintenance of psoriatic human skin on congenitally athymic (nude) mice.J Invest Dermatol. 1975; 64: 307-312Abstract Full Text PDF PubMed Google ScholarCARD14, Caspase recruitment domain–containing protein 14; Dsg, desmoglein; ICAM-1, intercellular adhesion molecule-1; N-WASP, neutral Wiskott-Aldrich syndrome protein.The table depicts some general approaches and selected features of murine phenotypes with similarities to human psoriasis. It shows examples of different approaches to generating animal models of psoriasis. Besides spontaneous mutations, numerous genetically engineered models with phenotypic resemblances of psoriasis have been proposed.It is striking that many different approaches, for example, epidermal or vascular alterations, changes in cytokine patterns, or tampering with immune cell functions can lead to similar chronic inflammatory phenotypes. Some genetically engineered changes, for example, in HLA-B27 transgenic rats or JunB/c-Jun–deficient mice, can also lead to extracutaneous symptoms of psoriasis such as arthritis. Other models also show alterations that are not typical of psoriasis, such as fibrosis in TGF-β1 transgenic mice.More recently, topical immunological modulations have been used to model psoriasis, especially the application of imiquimod (Aldara cream). Although the skin inflammation generated in this way also shows some remarkable differences to psoriasis, this model is meanwhile very widespread due to its easy application.In many models, severity and penetrance are highly variable and can be heavily dependent on husbandry conditions and environmental influences. This has been shown for immunological transfer models as well as several genetically engineered models. The gene dose can also have a decisive influence on the phenotype, for example, in BMP-6 transgenic mice. In general, there are still very few, if any, controlled head-to-head comparisons of different models with each other or with human psoriasis, and so a direct comparison of the models with each other can hardly be derived from currently available data. Open table in a new tab CARD14, Caspase recruitment domain–containing protein 14; Dsg, desmoglein; ICAM-1, intercellular adhesion molecule-1; N-WASP, neutral Wiskott-Aldrich syndrome protein. The table depicts some general approaches and selected features of murine phenotypes with similarities to human psoriasis. It shows examples of different approaches to generating animal models of psoriasis. Besides spontaneous mutations, numerous genetically engineered models with phenotypic resemblances of psoriasis have been proposed. It is striking that many different approaches, for example, epidermal or vascular alterations, changes in cytokine patterns, or tampering with immune cell functions can lead to similar chronic inflammatory phenotypes. Some genetically engineered changes, for example, in HLA-B27 transgenic rats or JunB/c-Jun–deficient mice, can also lead to extracutaneous symptoms of psoriasis such as arthritis. Other models also show alterations that are not typical of psoriasis, such as fibrosis in TGF-β1 transgenic mice. More recently, topical immunological modulations have been used to model psoriasis, especially the application of imiquimod (Aldara cream). Although the skin inflammation generated in this way also shows some remarkable differences to psoriasis, this model is meanwhile very widespread due to its easy application. In many models, severity and penetrance are highly variable and can be heavily dependent on husbandry conditions and environmental influences. This has been shown for immunological transfer models as well as several genetically engineered models. The gene dose can also have a decisive influence on the phenotype, for example, in BMP-6 transgenic mice. In general, there are still very few, if any, controlled head-to-head comparisons of different models with each other or with human psoriasis, and so a direct comparison of the models with each other can hardly be derived from currently available data. The first and most obvious approach would be to identify a naturally occurring animal disease that resembles human psoriasis. Yet, except for a few reports of sporadic psoriasis-like conditions in nonhuman primates, dogs, and pigs,19Jayo M.J. Zanolli M.D. Jayo J.M. Psoriatic plaques in Macaca fascicularis.Vet Pathol. 1988; 25: 282-285Crossref PubMed Google Scholar,20Lowe N.J. Breeding J. Kean C. Cohn M.L. Psoriasiform dermatosis in a rhesus monkey.J Invest Dermatol. 1981; 76: 141-143Abstract Full Text PDF PubMed Google Scholar no animal seems to spontaneously develop psoriasis. Second, adding or augmenting key molecules or cell types to a healthy organism (eg, by genetic, immunological, or pharmacological manipulation, the latter including topical application of imiquimod or injection of inflammatory cytokines)