Murine models of psoriasis and its applications in drug development

Journal Pre-proof Murine models of psoriasis and its applications in drug development

Tingting Luo, Yang Ma, Wei Wei PII:

S1056-8719(19)30415-0

DOI:

https://doi.org/10.1016/j.vascn.2019.106657

Reference:

JPM 106657

To appear in:

Journal of Pharmacological and Toxicological Methods

Received date:

8 April 2019

Revised date:

29 September 2019

Accepted date:

5 November 2019

Please cite this article as: T. Luo, Y. Ma and W. Wei, Murine models of psoriasis and its applications in drug development, Journal of Pharmacological and Toxicological Methods (2019), https://doi.org/10.1016/j.vascn.2019.106657

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Murine models of psoriasis and its applications in drug development Tingting Luo, Yang Ma*, Wei Wei* Institute of Clinical Pharmacology of Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province,

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230032, China

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*Address correspondence and reprint requests to: Wei Wei or Yang Ma, Institute of

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Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-

230032, China +86-551-6516-1209;

Fax:

+86-551-6516-1209;

E-mail

address:

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Tel.:

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inflammatory and Immune Medicine, Ministry of Education, Meishan Road 81, Hefei,

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[email protected] or [email protected]

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Abstract Psoriasis is an autoimmune skin disease which characteristic of a well-demarcated, erythematous, raised lesion with silvery-white dry scale. Although the mechanism of psoriasis has not been fully understood so far, much progress has been made in understanding many of its complex potential mechanism, particularly the crucial role of the IL-23/Th17 axis. There are a large number of psoriasis models that reflect the complexity of the psoriasis mechanisms. In this review, we summarize various psoriasis mouse models, detail the features and molecular mechanisms of these mouse models, and discuss their strengths and limitations for psoriasis research. The development of mouse models of psoriasis provide an important basis for studying psoriasis pathogenesis and antipsoriatic drugs development. Therefore, the application of various psoriasis mouse models in antipsoriatic drug development are also discussed. Key word: Psoriasis; IL-23/Th17 axis; mouse model; application

1. Introduction Psoriasis is a common autoimmune skin disease that accounts for about 2-3% of the global population [1]. Plaque psoriasis, also called psoriasis vulgaris, is the most common type of psoriasis. Typical skin lesions of psoriasis vulgaris are plaques with

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distinct boundaries, erythema, raised lesions, silvery white scales. In addition to plaque psoriasis, there are other less common types of psoriasis such as guttate, inverse, pustular, erythrodermic, palmo-plantar, and drug-associated psoriasis [2]. Plaque psoriasis has a typical histopathological phenotype. Epidermal thickening and associated silver scales are on account of premature keratinocyte maturation and subsequent incomplete keratinization, which causes nuclear retention in the stratum corneum cells (parakeratosis). In addition, abnormal proliferation of basal keratinocytes leads to epidermal thickening (acanthosis) and epidermal ridge (papillomatosis) and loss of granular layer (hypogranulosis) [3]. The erythema of psoriatic lesions is caused by a large number of vasodilatation. There is also a typical inflammatory cell infiltrate in psoriasis which including an increased number of mast cells, dendritic cells (DCs), neutrophils and macrophages, and CD4+ T cells, CD8+ T cells [4].

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2. Pathogenesis of psoriasis

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Although psoriasis is one of the most studied autoimmune skin disease, its pathogenesis has not yet been fully understood. Keratinocytes, which undergo abnormal proliferation and differentiation, are key cellular players in the pathogenesis of psoriasis. For this reason, psoriasis was initially thought to be only due to dysregulated growth of skin epithelial cells (keratinocytes) [5]. Cutaneous inflammatory infiltrate was observed but not considered to be the key to psoriasis pathogenesis. The essential role of the immune system in the psoriasis pathogenesis are confirmed after the successful use of immunosuppressive agents (cyclosporine A (CsA), denileukin diftitox, alefacept) [6-9]. For many years, psoriasis has been classified as a Th1-mediated disease due to an increased production of IFN-γ found in psoriatic tissues [10]. However, anti-IFNγ therapy proved to be ineffective in preliminary clinical trials [11], leading to a need for more in-depth studies of the pathogenesis of psoriasis. Fortunately, with the identification of the Th17 subtype and the cytokine IL-23, which promotes the Th17 polarization, the role of the IL-23/Th17 axis in the pathogenesis of psoriasis is becoming more and more important [12].When faced with skin trauma [13] or bacterial/viral infections [14, 15], keratinocytes and other immune (such as neutrophils) release cathelicidin antimicrobial peptide LL-37 [16], which forms a complex with nucleic acids (DNA and RNA) and then released by keratinocytes. The complexes stimulate plasmacytoid dendritic cells (pDCs) activation, followed by releasing IL-23 and IL-12 [17], which stimulating Th17, Th22 and Th1 activation [18]. IL-23 promote the polar Th17 response followed by the release of proinflammatory cytokines, such as IL-17A, IL-17F, IL-26, IL-29 and TNF-α [19]. IL-17A, IL-17F acting on keratinocytes result in epidermal hyperplasia, acanthosis, and hyperparakeratosis. IL-22 released by Th22 cells also contributes to epidermal hyperplasia. IL-17 acts alone or synergistically with TNF-α induces many psoriasisrelated genes transcription in keratinocytes [20]. These include the CCL20, which can regulate the skin recruitment of Th17 and DCs; LL-37 autoantigen; CXCL1, -2, -3, and -8 chemokines, which lead to the influx of various immune cell populations (e.g., neutrophils, macrophages, DCs, and CCR6+ cells) into skin; IL-19 and IL-36, which

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can promote keratinocyte hyperplasia; and antimicrobial peptides includingβ-defensins and S100A family. IL-26 and IL-29 are IFN-like cytokines which released by Th17 cells, they can activate STAT1 in keratinocytes, leading to expression of CXCL9, CXCL10, and CXCL11, then Th1 cells are recruited into skin. This self-amplifying “feed-forward” mechanisms inflammatory response are produced by activation and upregulation of IL-17 in keratinocytes. By inducing keratinocyte proliferation, altering terminal differentiation and infiltration of Inflammatory cell in the skin, ultimately leading to the development of mature psoriatic plaques. [21-23]. (figure 1)

Figure 1. The ‘IL-23/Th17 axis’ model for psoriasis. (1).skin trauma or bacterial/viral infections cause

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keratinocyte release LL-37 and nucleic acids which combine to form a complex that activates dendritic cells to secrete IL-23, IL-22. (2).IL-22 promotes the polarization of Th1 cells, IL-23 promotes the polarization of Th17 cells,

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and also stimulates Th22 cells. (3) Activated Th17 cells release cytokines IL-17A, IL-17F, IL-26, IL-29 and TNF. IL-17A, IL-17F and IL-22 released by Th22 cells promotes keratinocyte proliferation and IL-17 acts alone or synergistically with TNF-α induces many psoriasis-related genes transcription in keratinocytes, including CCL20, CXCL1, -2, -3, and -8 chemokines,β-defensins and S100A family. (4).IL-26 and IL-29 activate STAT1 in keratinocytes, leading to expression of CXCL9, CXCL10, and CXCL11, which recruit Th1 cells into skin.

3. Murine models of psoriasis Over the past few decades, a large number of models of psoriasis have been reported. These models accelerate our speed of further research into the mechanisms of psoriasis. More importantly, the application of psoriasis animal models greatly promotes the discovery and development of drugs. In this review, we present a variety of current psoriasis mouse models, describe the causes of models formation, mouse skin phenotypic changes, and histopathological changes of these models (Table 1), as well as plentiful antipsoriatic drugs developed by using a mouse model of psoriasis (Table2). The mouse model of psoriasis can be divided into spontaneous, genetically engineered (both transgenic and knockout), xenotransplantation, and directly induced approaches.

Journal Pre-proof Discussion of these models follows in the subsequent sections. Table 1. Summary of various mouse models and their similarities with human psoriasis Mouse model

Hyperkeratosis

Y

Y

Y

Y

Y

Y

/Scd1 )

ab

Y

Y

N

N

ND

ND

Y

[26]

fsn

fsn

Y

Y

N

Y

Y

ND

Y

[29]

Y

Y

N

Y

Y

Y

Y

[36]

CD18 PL/J TgIL1.1

Y

Y

Y

Y

Y

Y

Y

[42]

Y

Y

Y

Y

Y

ND

N

[46]

Il1rn(−/−)

Y

Y

Y

Y

Y

ND

Y

[47]

K14-VEGF

Y

Y

Y

Y

Y

Y

Y

[48]

KC-Tie2

Y

Y

Y

Y

Y

ND

Y

[51]

K5-JunB/c-Jun

Y

Y

Y

Y

Y

Y

Y

[54]

K5.TGFβ1

Y

Y

Y

Y

Y

ND

Y

[55]

K5-SRF mutant

Y

Y

Y

Y

ND

Y

ND

[57]

K5-IκBα-deficient

Y

Y

Y

Y

Y

Y

Y

[59]

K14-IKK2

Y

Y

Y

ND

Y

Y

ND

[61]

K5.Stat3C

Y

Y

Y

Y

Y

Y

Y

[64]

K5-IL-17C

Y

Y

Y

Y

Y

Y

Y

[66]

Y

Y

Y

Y

Y

Y

Y

[67]

DC-IL-17A K14-P40

Y

Y

Y

Y

Y

Y

Y

[68]

Y

N

Y

Y

ND

Y

Y

[70]

K14-TNF

Y

Y

ND

ND

ND

Y

ND

[71]

K14-KGF

Y

Y

N

N

N

Y

N

[72]

Athymic nude mouse

Y

Y

Y

Y

Y

SCID mouse

Y

Y

Y

AGR129 mouse

Y

Y

Y

IMQ-induced model

Y

Y

Y

IL-23-injected model

Y

Y

Y

IL-21-injected model

ND

N

Y

ab

Flaky skin(Ttc /Ttc ) cpdm/cpdm hypo

ind/+

K14-IL-17A

ind

Xenotransplantation models

Direct Induction Models

Vascularization Reference

Y Asebia(Scd1

Genetically engineered mouse models

Cytokine expression

microabscesses

f

Spontaneous model

Epidermal Neutrophil T cell infiltration infiltration

Y

Y

[78]

Y

Y

Y

Y

[81]

Y

Y

Y

Y

[75]

Y

Y

Y

Y

[88]

Y

Y

Y

Y

[91]

ND

ND

Y

N

[93]

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Human psoriasis

Acanthosis

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Y, phenotype present; N, phenotype absent; ND, not determined; Cpmd: chronic proliferative dermatitis; Tie2, angiopoietin receptor Tie2; VEGF, vascular endothelial growth factor; TGF, transforming growth factor; SRF, serum

interleukin;

TNF, tumor necrosis factor;

keratinocyte

growth factor;

SCID,

severe

combined

Pr

immunodeficiency; IMQ: imiquimod.

KGF,

e-

response factor; IκB, inhibitor of κB; IKK, IκB kinase; STAT, signal transducer and activator of transcription; IL,

Table 2. Psoriasis mouse models application in drug development Mouse model

Administration

The asebia mouse

subcutaneous injection

against inflammatory cells infiltration, especially mast cells

[28]

Delphinidin

Flaky skin mouse

topical application

enhance the expression of JunB and caspase-14

[31]

Helminth glycan LNFP III

Flaky skin mouse

subcutaneous injection

reduce expression of IFN-γ and turn the CD4/CD8 ratio close to be normal

[35]

Calcipotriene

cpdm/cpdm mouse

topical delivery

reduce epidermal hyperplasia and the levels of eosinophils

[39]

Etretinate

cpdm/cpdm mouse

intragastric administration

not very effective

[39]

Corticosteroids

cpdm/cpdm mouse

topical delivery

reduce epidermal hyperplasia and the levels of eosinophils

[39]

Dapsone

cpdm/cpdm mouse

intragastric administration

decrease epidermis thickness

[39]

Loratidine

cpdm/cpdm mouse

intragastric administration

inhibit the pruritus

[39]

Capsaicin

cpdm/cpdm mouse

topical delivery

reduce epidermal thickness

[39]

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hypo

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Therapies Cyclosporin A

Reference

CD18

intragastric administration

decrease the expression of Th17-related cytokines and phosphorylated STAT5

[44]

VEGF Trap

K14-VEGF mouse

subcutaneous injection

antagonismVEGF and eliminate hyperplastic vascular phenotype

[48]

K14-VEGF mouse

transdermal delivery

inhibit the expression of ICAM-1, VCAM-1 and E-selectin and inflamed blood vessels

[49]

K14-VEGF mouse

topical delivery

inhibit p38, ERK1/2 and AKT signaling pathways

[50]

KC-Tie2 mouse

intradermal injection

decrease dermal angiogenesis and returne the expression of CD8 + T cell, IL-1α, IL-6, IL-23 and TNF-α to normal levels

[52]

K5.TGFβ1wt mouse

topical delivery

decrease the levels of TGF-β1, IL-6, IL-23, IL-17A

[56]

K5.Stat3C mouse

intragastric administration

decrease the expression of IL-17A, without affect the expression of IFN-γ

[65]

HK Clodronate liposome with consumption of APCS Smad3 inhibitor SIS3 RORgt antagonist A213

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JAK 1/JAK3 inhibitor R348 UCL/mIL-4

PL/J mouse

specific pathway or aspect of the pathology

+

+

TNF-a inhibition (CNTO5048)

K5-IL-17C mouse

injection

reduce infiltration of CD4 and CD8 T cell counts as well as the levels of IFN-γ, IL-6 and IL-1β

IL-17A neutralizing antibody (BZN035)

K14-IL-17Aind/+ mouse

injection

not very effective

[69]

[66]

IL-17A neutralizing antibody (BZN035)

DC-IL-17A

injection

decrease the level of IL-6, IL-22, and TNF-α and reverse vascular dysfunction

[69]

Cyclosporin A

SCID mouse

intraperitoneal injection

reduce the epidermal thickness

[77]

anti-CD11α

SCID mouse

intraperitoneal injection

reduce the epidermal thickness

[77]

Clobetasol propionate

SCID mouse

topical delivery

reduce the epidermal thickness

[77]

Bz-423

SCID mouse

topical delivery

inhibit keratinocyte proliferation

[83]

AZ17

SCID mouse

intraperitoneal injection

improve the epidermal thickness, vessel occurrence and lymphocyte infiltration

[84]

GRh2

AGR129 mouse

subcutaneous injection

decrease the level of VEGF-A

[85]

Delphinidin

IMQ-induced mouse

topical delivery

reduce the activation of PI3K/Akt/mTOR pathway

[89]

ZnPc-F7-PDT

IMQ-induced mouse

photodynamic therapy

decrease the levels of PCNA, Bcl-2 increased the level of Bax

[90] [69]

ind/ind

mouse

IL-17A neutralizing antibody (BZN035)

IMQ-induced mouse

injection

decrease the infiltration of myeloid cells, neutrophils, macrophages and the levels of IL-6, IL-22 and IL-1β

Anti-IL-12p40 antibody(h6f6)

IL-23-induced mouse

intraperitoneal injection

inhibit the inflammatory response and reduce epidermal hyperplasia

[92]

AZ17

IL-23-induced mouse

intraperitoneal injection

inhibit the ear inflammation

[84]

RORgt antagonist A213

IL-23-induced mouse

intragastric administration

+

reduce the percentage of Th17 cells and CD4 T cells and levels of IL-17A, IL-22

[65]

LNFP III: lacto-N-fucopentaose; BoNT-A: botulinum neurotoxin A; UCL/mIL-4: transdermal delivery of IL-4 using ultradeformable cationic liposome; HK: Honokiol; Clodronate liposomes: depletion of antigen-presenting cells by clodronate liposomes; Bz-423:7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)-4,5-dihydro-

Journal Pre-proof 1H-benzo[b][1,4]diazepin-2(3H)-one; GRh2: Ginsenoside Rh2; Anti-IL-12p40 antibody (h6F6): antibody inhibitied IL-12–IL-12Rβ2 and IL-23–IL-23R, humanized variant of 6F6; ZnPc-F7-PDT: Α-(8-Quinolinoxy) Zinc Phthalocyanine-Mediated Photodynamic Therapy; AZ17: a new bispecific drug targeting IL-6 and IL-23.

3.1 Spontaneous Mouse Models

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Homozygous asebia (Scd1ab/Scd1ab) mice, the first murine model of hyperkeratosis was reported in 1965[24]. Due to mutation of the Scd1 gene, the lack of the sebaceous glands is a characteristic feature in asebia mice [25], other changes including epidermal acanthosis, increased dermal vascularity, and a infiltration of macrophages and mast cells in dermal, and there are high density fibroblasts in the dermis. Asebia mice can be used as an epidermal hyperproliferation model to evaluate the role of antiproliferative drugs. However, there are no T cells and neutrophils in the dermis and epidermis of asebia mouse, its application in antipsoriatic drug research has been limited [26]. The asebia mouse model is based on epidermal hyperproliferation, while the treatment of asebia mouse with Anthralin and tar with UVB which can improve human psoriasis increase, rather than reduce, epidermal hyperproliferation of asebia mice. This apparent paradox may illustrate the epidermal hyperproliferation seen in human psoriatic skin may not be a primary event but secondary to the dermal inflammation that is seen in that disease [27]. Since asebia mice have inflammatory cells infiltration, especially mast cells, one report used asebia mice to evaluate the anti-inflammatory effects of CsA, especially against mast cells. After treatment with CsA in asebia mice, the number of mast cells decreased 4.5-fold in a dose-dependent manner. CsA treatment also reduced epidermal hyperplasia, dermal cells and edema, and restored the skin phenotype of mice to normal wild type. These results show that CsA may be used to treat mast cellmediated diseases [28]. Due to an autosomal recessive mutation in flaky skin (fsn/fsn) mice, the mice skin show epidermal hyperplasia and skin inflammation. The infiltration of inflammatory cells including lymphocyte, neutrophils and macrophage. At the same time, neovascularization can also be observed. It is worth noting that the pathogenic role of neutrophils in fsn/fsn mice is similar to that seen in human skin diseases [29]. This model is useful for evaluating angiogenesis and keratinocyte proliferation However, CsA treatment was not effective for fsn/fsn mice [30] One study reported that this model was used to evaluate the therapeutic effect of delphinidin. After treated with delphinidin in fsn/fsn mice, the expression of pathological markers of psoriatic lesions and the levels of inflammatory cells and cytokines were significantly reduced. More importantly, the expression of JunB and caspase-14 which has been reported to be greatly reduced in psoriasis skin were enhanced after treatment with delphinidin [3134]. As an immunomodulatory molecule, helminth glycan lacto-N-fucopentaose (LNFP III) has an effect of driving CD4+ Th2 type bias and immunosuppression. After treatment of fsn/fsn mice with LNFP III, skin damage was improved, and the epidermis thickness returned to normal levels. In addition, LNFP III reduced expression of IFNγ, macrophage and turned the CD4/CD8 ratio close to be normal in fsn/fsn mice, which may explain the part of therapeutic mechanism of LNFPII in this model [35].

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The formation of a mouse model of chronic proliferative dermatitis (cpdm/cpdm) is due to spontaneous mutation of Sharpin exon 1 in C57BL/Ka mice, this model shows a variety of features like psoriasis. This model develop psoriatic phenotype at the age of 5 to 6 weeks which is characterized by epidermal hyperplasia and infiltration of granulocytes and macrophage, and microabscesses formation can be observed. In addition, there are dilatation and proliferation of dermal capillaries and the number of mast cells in the dermis gradually increases as the mouse ages [36]. However, the development of inflammation in cpdm/cpdm mouse is independent of T and B cells and is driven by Th2 cytokines such as IL-4, IL-5 and IL-13. [37-38]. A study reported the therapeutic effects of six drugs on the cpdm/cpdm model. These drugs includes calcipotriene and etretinate which are directed against epidermal hyperplasia; corticosteroids and dapsone which have an anti-inflammatory effects and loratidine and capsaicin which have an anti-pruritus effect. Both calcipotriene and topical corticosteroids reduced cpdm/cpdm mice epidermal hyperplasia and the levels of eosinophils. Treatment of the systemic etretinate were not very effective. Treatment of the dapsone decreased the BrdU incorporation and the epidermis thickness. The loratidine ameliorated the skin lesions probably by inhibiting the pruritus. Capsaicin improved the skin lesions and reduced epidermal thickness. Due to the limited participation of T cells, anti-psoriatic drugs have no obvious effect on the treatment of this model, but they can be used to study the application of new drugs in certain aspects, such as epidermal hyperplasia, eosinophil infiltration and itching [39].

3.2 Genetically engineered mouse models

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Gene engineering models account for the largest proportion of psoriasis models, including knockout mouse models, which knockout (loss-of-function) of specific genes and their products, and transgenic model, which overexpression (gain-of-function) specific genes. The genetically engineered psoriasis mouse models are usually directed at a single gene, so it can only mimic the selected aspects of psoriasis that does not fully reflect the complexity of psoriasis. Most of these models by controlling the promoter of the epidermal layer such as keratin gene keratin 5 (K5), K14, K10 or involucrin to overexpress or knockout of specific genes to induce spontaneous formation of a psoriasis-like skin disease [40]. The CD18 hypomorphic (CD18hypo) PL/J mouse model was established in the early 1990s by CD18 subtype mice on the PL/J strain background [41]. The expression of CD18hypoPL/J mouse common chain of β2-integrin (CD11/CD18) was only 2-16% of wild-type level. CD18hypoPL/J mouse are characterized by hyperplasia of keratinocytes, the presence of microabscess, expanded blood vessel, and the infiltration of CD4+ T cells in the skin lesions [42]. It is reported that decreased CD18 expression hinders the interaction between Tregs and DC. This causes Treg cells dysfunction, which prevents it from inhibiting pathological T cells, thereby it cannot prevent disease progression and deterioration. By adoptive transfer of Tregs expressing wild-type CD18 levels into this model, skin damage can be reversed [43].Treatment of CD18hypoPL/J mice with JAK1/JAK3 inhibitor R348 showed a marked decrease in skin lesion and lymphocytes

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infiltration including CD4+, CD8+, and CD25+ T cells. The psoriasiform skin lesions and histological features of the CD18hypoPL/J mice were reversed in a dose-dependent fashion. Furthermore, Th17-related cytokines expression, such as IL-17, IL-22, IL-23 and TNF-α were also decreased dramatically in this model treated with R348, and phosphorylated STAT5 expression was reduced following IL-2 stimulation [44]. As a pro-inflammatory cytokine, IL-1 plays an important role in the development of Th17 cell responses in psoriasis, it synergizes with IL-23 to induce IL-17 production by T cells [45] .Mice overexpression of IL-1α in the basal keratinocytes (TgIL1.1 mice) can form a psoriasiform skin, including hair loss, scaling, parakeratosis, and inflammatory cell infiltration in involved skin. Histologically, hyperkeratosis and dermal mononuclear cell infiltration are seen in non-lesional skin [46]. In the same case, IL-1 receptor antagonist-deficient (IL1rn-/-) BALB/c mice exhibit similar psoriasis phenotypes. The mice epidermis become thickened and immature keratin K6 expression are observed throughout the process. The stratum corneum shows parakeratotsis and neutrophil-rich microabscesses forming beneath it. There are infiltration of leukocytes, dendritic cells and T cells in dermis and epidermis. In an addition, neovascularization can also be seen in the dermis [47]. The red appearance of psoriasis lesions is caused by dermal vascular proliferation, vascular endothelial growth factor (VEGF), which is an effective mediator of angiogenesis are dramatically enhanced in psoriasis skin. Studies have shown that chronic transgenic delivery of VEGF to the mice epidermis driven by the K14 promotor (K14-VEGF-mice) can lead to severe inflammatory conditions in mouse skin. In addition, epidermal abnormality, and increased angiogenesis can be observed in K14VEGF-mice. Specific endothelial cell adhesion molecules including E-selectin, VCAM-1, and ICAM-1 which are markers of vascular inflammation and hyperplasia in human psoriasis, also dramatically increased in K14-VEGF-mice.These results suggest that excess VEGF may provide a propensity to induce vascular inflammatory responses and then prone to broader tissue inflammation that is very similar to the psoriasis state. K14-VEGF mice treated with VEGF Trap, a specific VEGF antagonist, resulting in eliminating the proliferative vascular phenotype and inhibiting the associated inflammatory state, which possibly providing a novel therapeutic strategy in treating psoriasis [48]. Treatment of Topical transdermal delivery of IL-4 using ultradeformable cationic liposome (UCL/mIL-4) are resistant to psoriasis in this model. UCL/mIL-4 treatment reduced the expression of ICAM-1, VCAM-1 and E-selectin in K14-VEGF mice, and the proliferative and inflamed mouse blood vessels were inhibited [49]. In addition, Honokiol (HK) which has effects of anti-inflammatory and anti-angiogenic also showed anti-psoriatic effects in K14-VEGF mice model. Topical treatment with HK cream effectively improved the features of psoriasis in K14-VEGF mice. The expression of CD4+ T cells, TNF-α and IFN-γ were obviously decreased, but the levels of IL-4 and IL-10 was not affected. Moreover, HK also inhibited the activation of nuclear p65, VEGFR-2 and related phosphorylated proteins such as pVEGFR-2, p-ERK1/2, p-AKT and p-p38. This study may help us better understand the

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relationship between inflammation and angiogenesis in psoriasis [50]. The KC-Tie2 mice overexpressing the angiopoietin receptor Tie2 in keratinocytes driven by the K5 promoter spontaneously form a psoriasis skin phenotype. This model clearly mimics signaling pathways in human psoriasis, including activation of Stat3 and release of downstream inflammatory cytokines. The expression of phosphorylated STAT3 and the levels of cytokines associated with psoriasis including IL-17, IL-22, IL23, INF-γ and TNF-α are up-regulated in the KC-Tie2 mouse. Moreover, the KC-Tie mouse skin blood vessels are greatly increased, and the level of VEGF also increased. Doxycycline treatment (inhibition of Tie2) reversed the skin phenotypes, and the antigen presenting cells (APCs) as well as associated cytokines are obviously decreased. While CsA treatement just improved (not reversed) the KC-Tie2 mouse skin lesions, and the APCs still keep in high levels. Therefore, it can be speculated that APCs may exert a crucial role in maintaining the psoriasis-like phenotype in KC-Tie2 mice [51]. A report demonstrated that consumption of APCs using clodronate liposomes reverse the psoriasis-like skin disease in KC-Tie2 mice. Intradermal injection of liposomes in KC-Tie2 mice abolished CD11c+, F4 /80+ and CD11b+ cells in the skin and restored the number of CD8+ T cell to normal levels. The KC-Tie2 mice acanthotic skin phenotype get relieved. In addition, the dermal angiogenesis was decreased, and levels of cytokines such as IL-1α, IL-6, IL-23 and TNF-α returned to normal levels, meanwhile IFN-γand IL-17 reduced modestly [52]. JunB, a part of the AP-1 transcription factor, is located in the psoriasis susceptible region PSORS6 [53]. The K5-c-Jun deletion mouse model, which knockouts JunB and its functional companion c-Jun in epidermal cells of adult mice causes a phenotype similar to psoriasis and arthritis. The levels of pro-inflammatory cytokines such as IL1, IFN-γ, IL-12p40 and TNF-α are up-regulated, and various chemokines such as MIP2, MIP-1a, MIP-1b, IP-10 and MCP-1 are also highly expressed. In this model the expression of the chemotactic protein S100A8 and S100A9 dramatically increased, which can recruit neutrophils and macrophages to the epidermis, promoting the formation of psoriasis-like lesions. This is considered to be the decisive early event in this model for the formation of a psoriasis phenotype [54]. Overexpression of TGF β1 using the keratin 5 promoter in the epidermis leads to the formation of psoriasiatic skin disease similar to psoriasis in K5.TGFβ1 wt mouse model. The K5.TGFβ1wt mouse skin first appears psoriasis-like inflammation. In K5.TGFβ1wt mouse the levels of chemokines MIP-2, MIP-1a, MIP-1b, IP-10 and MCP-1 are upregulated, which have potent chemotaxis to T cells and neutrophils. Meanwhile, TGF β1 can promote angiogenesis through the ALK1 signaling pathway. While the skin lesions is caused by previously produced inflammatory cells and inflammatory factors [55]. Smad3 inhibitor (SIS3) prominently inhibits TGF-β/Smad3 signaling and skin lesions in K5.TGFβ1wt mice. After treatment with SIS3 the psoriasis-like lesions were improved and infiltration of T cells and macrophages were reduced. The expression of TGF-β1, IL-6, IL-23, IL-17A were also marked decreased in K5.TGFβ1wt mice [56]. Serum response factors (SRF) is a transcription factor which are respond to

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mitogenic stimuli and stress conditions. SRF is highly expressed in keratinocytes in normal human, but strongly decreases in hyperproliferating epidermis. A reduction in SRF expression can severely affect epidermal homeostasis by disrupting the cytoskeleton and subsequent cell-cell and cell-matrix adhesion. This can trigger an inflammatory response that in turn induces excessive proliferation of keratinocytes. Keratinocyte-specific deletion SRF (SRF-mutant skin) spontaneously form psoriatic skin lesion, and the levels of IL-1β and chemokines such as S100A8 and S100A9 are strongly increased in SRF-mutant skin [57]. Nuclear transcription factor B (NF-κB) plays a critical role in defense of the host against specific pathogens and is also pivotal for normal immune function. It exists in the cytoplasm in an inactive form and binds to IκB regulatory proteins (including: IκBα、 IκBβ、IκBε, ect.)which is mediated by IκB kinase (IKK). IKK consists of the three subunits IKK-1, IKK-2 and IKK-γ [58]. Mouse with keratinocytes and T cells deficient in IκBα develops a severe inflammatory skin disease, with thickened epidermis and enhanced expression of Ki67, CD4+ T cells, CD8+ T cells, Gr-1+ neutrophils and macrophages. The targeted deletion of RelA (a member of the NF-κB family) in this mouse keratinocyte reverses the disease, demonstrating the important role of NF-κB in the interaction of keratinocytes and T cells in skin inflammation [59]. Another kind of transgenic model about NF-κB is K14-Cre-IKK2fl/fl mice, whose epidermis specific delete IKK2, leading to a severe psoriasis-like disease, which depend on the TNF-αmediated inflammatory response. These mice skin develop epidermis hyperplasia and inflammatory cells infiltration, especially the levels of IL-1 and TNF are elevated. When K14-Cre-IKK2fl/fl mice lacks TNFR1, its skin disease can be reversed, which proves that TNF plays an important role in the development of this model disease [60]. Eliminate skin macrophages in K14-Cre-IKK2fl/fl mice significantly improved psoriatic skin chances. This indicates that the involvement of macrophages also plays an important role in the K14-Cre-IKK2fl/fl model [61]. Signal transducer and activator of transcription 3 (Stat3) exerts a vital role in inflammatory and immune responses. Furthermore, in psoriasis, phosphorylated and overactivated of STAT3 promotes Th17 polarization by activation of IL-23, which is the main pathogenesis of psoriasis [62-63]. Activated STAT3 is significantly increased in human psoriasis skin, Similarly, Overexpression of activated STAT3 in mouse keratinocytes (K5.Stat3C mice) also develop a similar phenotype to psoriasis. Increased expression of some psoriasis-related factors in K5.Stat3C mice, including VEGF (more than twofold), TGF-α, ICAM1 and Nfkbia. Transplantation of the K5.Stat3C mice skin into athymic nude mice and simultaneous injection of activated T cells can produce psoriasis lesions. While normal mouse skin transplantation and no injection of T cells can not cause athymic nude mice skin psoriasis-like damage [64]. RORγt antagonist A213, which inhibits the RORγt expression in Th17 cell both in human and murine in vitro had an antipsoriatic effect on K5.Stat3C mice. Treatment with A213 resulted in an improvement in scale and erythema signs, and a decrease in ear thickness. The inflammatory cell infiltration were also reduced. Moreover the expression of IL-17A in

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the lesions and skin-draining lymph nodes were significantly decreased while the TFNγ expression was not affected. This suggests that RORγt antagonist A213 would be a promising drug for the treatment of psoriasis [65]. Numerous clinical and experimental data have been identified IL-17 as vital players in psoriasis. Mouse overexpressing IL-17C in keratinocyte (K5-IL-17C transgenic mice) exhibits marked thickened epidermis and neovascularization in involved skin. The expression of TNF-a, IL-1α/β, IL-17A/F, IL-23p19, VEGF, IL-6, and CCL20 are upregulated in involved skin. TNF-α inhibitor reduce K5-IL-17C mice epidermal thickness and infiltration of CD4 + and CD8 + T cell counts as well as the levels of IFNγ, IL-6 and IL-1β [66]. Model of transgenic IL-17A expression targeting mice (K14-IL-17Aind/+) can be achieved after crossing IL-17Aind allele with the K14-Cre strain. Likewise, the transgenic mice inevitably develop an apparent psoriasis-like skin disease. In addition, this model not only shows typical psoriatic conjunctivitis and arthritis comorbidities also develops vascular dysfunction and increased levels of oxidative stress in vessel. The levels of ROS and NADPH oxidase activity are increased, the inflammatory cell infiltration such as neutrophils and serum levels of IL-6 and TNF-α are also ehanced in this model. This suggests that K14-IL-17Aind/+ mice provide a useful tool for experimental analysis of psoriasis-like skin diseases and their complications. Both treatment of Etanercept (anti-TNFα) and anti-IL-6 improve the skin lesions and vascular dysfunction with the down-regulated expression of blood ROS and heart oxidase activity in this models [67]. In addition, DC-IL-17Aind mice with constitutive low-level expression of IL-17A by CD11c+ cells are obtained from IL-17Aind mice crossing to CD11c-Cre also result in development of psoriasis-like skin disease. The occurrence and progress of psoriatic skin lesions in DC-IL-17Aind/ind mice are IL-17A dose-dependent, and the lesions have infiltration inflammatory cell infiltration such as neutrophils, myeloid cells and CD4+ T cells. Similar to K14-IL-17Aind/+ mice, the DCIL-17Aind/ind mice also develop vascular dysfunction with increased levels of ROS/RNS [68]. Intriguingly, IL-17A neutralizing antibody failed to improve skin disease in K14IL-17Aind/ind mice. The skin lesion and infiltration of lymphocyte in the skin were not significantly lessened after treatment with IL-17A neutralizing antibody, even if the concentration was increased. In constrast, anti-IL-17A treatment eradicated cutaneous lesions of DC-IL-17Aind/ind mice. After injecting IL-17A neutralizing antibody for 4 weeks, the microabscess and thickened epidermal as well as hyperkeratosis in these mice were absent. Also, the infiltration of neutrophils and the level of proinflammatory cytokines, such as, IL-6, IL-22, and TNF-α were decreased. More importantly, anti-IL17A treatment reduced the formation of oxidative stress in peripheral blood and completely reversed vascular dysfunction in DC-IL-17Aind/ind mice. These findings provide a valuable reference for the prevention of cardiovascular risk in patients with psoriasis [69]. IL-12 and IL-23 play a vital role in the pathogenesis of psoriasis, both of them have p40 subunit. K14-p40-mice which continual express monomeric and homodimeric p40

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3.3. Xenotransplantations Models

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in epidermis using K14 promoter lead to psoriasis-like skin phenotype, there are many inflammatory cells increased in the skin lesions, including CD4+ T cells, macrophages, eosinophils and few neutrophils [70]. TNF-α is highly expressed in human psoriasis and promotes the development of the disease. Targeted therapy against TNF-α plays a very effective therapeutic role in the vast majority of patients. While Mice overexpressing TNF-α (K14-TNF-α model) stop gaining weight within 1 week postbirth and subsequently die within 3–5 weeks due to the inhibition of adipose production and intestinal and liver necrosis [71]. As a mitogenic intermediary, keratinocyte growth factor (KGF) can interact with many epithelial cells, especially keratinocytes, and its receptor plays an essential role in epidermal keratinocyte maturation and wound healing. On this account, establishing a K15/KGF mouse model is very promising. The K15/KGF mouse shows keratinocytes hyperproliferation. While the development of hair follicle and lipogenesis are strongly inhibited in this model. This model is limited in clinical studies because of its lack of immune response [72].

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The humanized xenograft model is the transplantation of involved or uninvolved skin of human with psoriasis into immunodeficient mice. It is another way to develop an animal model of psoriasis, which may be the only model that is similar to psoriasis in genetic, immune, and phenotypic changes. Due to the immunodeficiency of the recipient mouse, the implantation of immune cells is also essential when transplanting human skin [73-75]. Although the xenotransplantations models has been widely used, inevitably, there are many technical problems and instability in the establishment of xenotransplantations models. In addition to the need for adequate skin samples for psoriasis patients, the xenotransplantations models also presents a major challenge in the large heterogeneity of transplanted skin samples. In fact, genetic background, body parts and other factors may seriously affect the study results [76].Inconsistent thickness of skin lesions, different skin areas and other factors in transplant patients, will produce variability in the establishment of the xenotransplantations models. Reducing the size of the transplanted skin is one possible way to reduce tissue limitations. However, this approach is limited by the ability to surgically process tissue pieces and too small fragments may be over-growth by adjacent mouse skin [77]. The athymic nude mice were the first psoriatic xenotransplantation model developed in 1981, and were originally used to illuminate the difference between involved and uninvolved skin [78]. Athymic nude mice lack T cells, although B cells are not directly affected, but the humoral response is inhibited, which may be caused by the lack of functional T helper cells. The T cells population, grafts (even tissues obtained from other species) can be maintained without being rejected. Transplanting the skin of psoriasis patients to the nude mice, the mice show the characteristics of psoriasis in the transplanted skin. The skin are characterized by thickened epidermal and papillomatosis, and this feature will last for more than 2 months. However, there are still some features that are different from human psoriasis, such as preservation of the

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stratum corneum and absence of parakeratosis [79]. Mice with severe combined immunodeficiency (SCID) are extensively used as models in psoriasis research. Due to mutations in DNA-dependent protein kinases (protein kinase, DNA-activated, catalytic polypeptide, Prkdcscid), SCID mice lack of both T cells and B cells. Graft human skin onto SCID mice exhibits some the psoriasis phenotypic features including thickened epidermis and infiltration of inflammatory cells [80]. Co-injection of immune cells from patients with psoriasis can maintain the features for a longer period of time [81]. In addition, a report has shown that coinjection of circulating CD4-positive lymphocytes from patients with psoriasis not only reserves the characteristics of psoriasis in lesions, but also induces the psoriasis phenotypes in non-lesional skin [82]. A report evaluated the anti-psoriatic effects of three drugs on this model: (1) anti-CD11α; (2) CsA; (3) clobetasol propionate (Temovate). These three agents can be given after transplanting normal human or psoriasis lesional skin to the skin of SCID mice for 3 to 5 weeks. CsA and anti-CD11α reduced the epidermal thickness of transplanted psoriatic skin but both of them cannot reduce the thickness of transplanted normal skin and CsA is more effective. This may be due to the wide-ranging effect of CsA on T cell function, whereas treatment against CD11a may only act on cell-cell interactions that are dependent on this receptor. Clobetasol propionate which has the function of inhibiting cell growth and inducing skin atrophy alleviated the epidermal thickness of both involved and uninvolved skin [77]. Also, a report demonstrated that Bz-423 which is a benzodiazepine exhibited antipsoriatic effect on this model. BZ-423 had cytotoxic and cytostatic effects on many cells, it reduced epidermal hyperplasia after transplantation human psoriatic skin or nonpsoriatic skin to SCID mice, however it does not reduce normal skin thickness. Bz423 reduced epidermal hyperplasia in the SCID mouse transplantation model mainly by inhibiting keratinocyte proliferation. This effect appears to be mediated by the oxidant, leading to subsequent inhibition by the growth promoting signaling pathway [83]. Because IL-6 and IL-23 can promote the differentiation of Th17 cells, they are considered to be important mediators for the development of psoriasis. AZ17 is a bispecific molecule targeting monoclonal antibodies to human IL-6 and IL-23. AZ17 improved the epidermal thickness, vessel occurrence as well as lymphocyte infiltration in epidermal and dermal of SCID mice [84]. There is also a xenograft model that transplants human psoriasis skin into AGR129 mice. Due to the lack of type I and II IFN receptors and recombinase activation gene2, AGR129 mice lacking B and T lymphocytes and have immature NK cells. Engraftment of symptomless prepsoriatic human skin into these mice leads to the spontaneous development of psoriasis-like phenotype and does not require T cell injection. Resident human T cells in prepsoriasis skin undergo local proliferation after implantation, which is vital to development of the psoriasis-like skin disease [75]. A report had demonstrated that Ginsenoside Rh2 (GRh2) exhibited antipsoriatic effect on AGR129 mice. After treatment with GRh2 on the skin graft, the acanthosis and papillomatosis index, percentage of T lymphocyte as well as vessel density in AGR129

Journal Pre-proof mice skin grafts are decreased dose-dependently. Moreover GRh2 decreased the level of VEGF-A, which is a major mediator of neovascularization in the skin grafts. This study used sFlt1, which inhibits VEGF-A signaling to treat AGR129 mouse transplant models. It was found that sFlt1 and GRh2 have a very similar effect on AGR129 mice. These findings suggest that GRh2 inhibits psoriasis-like features may be due to inhibition of neovascularization by down-regulating VEGF-A signaling pathways [85].

3.4. Direct Induction Models

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Initially, imiquimod (IMQ) cream is used to topically treat genital and perianal spasm caused by human papillomavirus. Clinical studies have found that the use of IMQ on patients with psoriasis accelerates the appearance of psoriasis lesions, whether at the site of use or at an unaffected site. IMQ, a Toll-like receptor 7 ligand, has powerful immune activation on macrophages, monocytes and plasmacytoid dendritic cells (pDCs). Clinically, long-term use of IMQ can worsen the symptoms of psoriasis in patients with psoriasis, and the deterioration occurs in the treated area or even the distant skin parts that have not been affected before [86, 87]. For this reason, using IMQ to induce psoriasis in mice becomes an effective animal model of psoriasis. BALB/c mice are coated with 5% IMQ at dose of 62.5 mg on the back skin (with hair removal) for 5-6 days. Similar to humans, there is also a human psoriasis-like appearance on the back of IMQ-treated mice. The back skin are characterized by erythema, epidermal thickening, scales, acanthosis, parakeratosis, and neovascularization as well as inflammatory infiltration by T cells, neutrophils, DCs and pDC. Moreover, When IMQ induced mice lacking IL-23p19 or IL-17RA, the skin of the mice did not show any skin inflammation, which convincingly demonstrates the key role of the IL-23/IL-17 axis in IMQ-induced skin disease [88]. In human psoriasis and IMQ-induced mouse psoriasis model, PI3K/Akt/mTOR signaling pathway activation is abnormally elevated. Delphinidin is a potent antioxidant with pro-apoptotic, antiproliferative, anti-inflammatory and differentiation-promoting effects. It inhibits the PI3K/Akt/mTOR signaling pathway both in vitro and in vivo. Topically treated with delphinidin of IMQ-induced mice resulted in significantly decreasing in ear thickness and epidermal thickness, and the psoriatic-like histological features improved significantly. The expression of proliferation markers, epidermal cornification markers as well as differentiation-related proteins tended to normalize after treated with delphinidin. The infiltration of immune cells and psoriasis-related cytokines/chemokines were lessened. The activation of PI3K/Akt/mTOR pathway also reduced in treated mice. These results suggest that inhibition of PI3K/Akt/mTOR signaling may be a promising therapeutic target for the treatment of psoriasis [89]. Α(8-quinolinyloxy) zinc phthalocyanine (ZnPc-F7) is a novel metal phthalocyanine coordination compound whose specific excitation source is 670 nm light, which can reach deeper skin layers and safer than UVA. Treatment with ZnPc-F7-mediated photodynamic therapy (PDT) in IMQ -induced psoriasis model resulted in inhibition of psoriasis skin hyperproliferation. The levels of PCNA, Bcl-2 were decreased, while the level of Bax were increased, which may be a potential mechanism to inhibit

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4. Conclusion

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hyperproliferation. Meanwhile IL-17A mRNA and IL-17F mRNA are downregulated after treatment with ZnPc-F7- PDT [90]. Antagonization of IL-17A can also exert antipsoriatic effect in imiquimod-induced psoriasis model. Under the treatment of anti-IL17A, the skin lesion formation in IMQ-treated mice was delayed and its severity was markly reduced. Anti-IL-17A treatment inhibited the infiltration of myeloid cells, neutrophils, and macrophages in IMQ-induced skin. The levels of proinflammatory cytokine such as IL-6, IL-22 and IL-1β were aslo decreased [69]. Injection IL-23 intradermally into mice triggers TNF-dependent but IL-17Aindependent cascade events leading to skin damage that shares many features with human psoriasis including erythema associated with epidermal hyperplasia, mixed dermal infiltration and infiltration of CD4+ lymphocytes, DC, neutrophils and macrophage [91]. A report demonstrated that a class of anti-IL-12p40 antibodies ameliorate the psoriasis phenotype of IL-23-induced mouse models by inhibiting IL12–IL-12Rβ2 and IL-23–IL-23R. Treatment with anti-IL-12p40 antibodies inhibited the inflammatory response and reduced epidermal hyperplasia in IL-23-induced mouse [92]. Administration of RORγt antagonist A213 also significantly attenuated acanthosis and dermal cell infiltrates, and mRNA levels of IL-17A and IL-22 in IL-23-induced mice. The number of IL-17-producing cells in skin-draining lymph node were also decreased under A213 administration. Furthermore, A213 dose-dependently reduced the percentage Th17 cells and CD4+ T cells [65]. In addition, treatement with AZ17 completely inhibited the ear inflammation in IL-23-induced mouse ear inflammation model [84]. Another cytokine injection mouse model is injecting IL-21 into mouse skin. Intradermal injecting IL-21 into mice stimulates proliferation of human keratinocytes and causes epidermal hyperplasia as well as the T cells accumulation in the skin [93].

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Psoriasis is an autoimmune disease whose characteristic phenotype is erythematous, raised lesion with silvery-white dry scale. Although the pathogenesis of psoriasis is not completely clear, IL-23 mediates the Th17 cells inflammatory response play a vital role. In this review, I mainly describe the mouse psoriasis model and its application in drug development. The main psoriasis mouse models are spontaneous models, genetically engineered mouse models, xenotransplantations models and direct induction models. Each model has its own characteristics and deficiencies, and they can be applied to the development of different drugs. Due to the lack of T and B cells, spontaneous models may not be suitable for studies of antipsoriatic drugs, but this model can be used to study other aspects such as epidermal hyperproliferation, mast cells and eosinophil infiltration, and itching. The genetically engineered mouse models are established by overexpressing or deleting the expression of a cytokine or protein, which does not reflect the pathological mechanism of psoriasis as a whole, but it is undeniable that in transgenic animal models, Overexpressed or deleted genes are important mediators in human psoriasis, such as the STAT3 protein and its downstream cytokines, which play a very important role in the pathogenesis of psoriasis. The drugs against these proteins

Journal Pre-proof have a good therapeutic effect. Although the xenotransplantations model is considered to be the most similar model to human psoriasis, there are many technical problems and instability in the establishment of xenotransplantations models. And due to lack of immune function in mice, the models requires the provision of exogenous T cells in addition to the need to transplant the skin of patients with psoriasis. The IMQ induction model has been widely used because of its ease of operation and low cost, but the disadvantage of this model is that it is only used as an acute model. Although no animal model can completely mimic human psoriasis, a more in-depth study of psoriasis will allow us to have a better understanding of the psoriasis pathogenesis and develop animal models that are more similar to human psoriasis, which ultimately provide a powerful experimental basis for the development of anti-psoriatic drugs.

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Acknowledgements

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This work was supported by grants from the National Natural Science Foundation

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CONFLICT OF INTEREST

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of China (No. 81673444; 81330081; 81502123),

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The authors declare no conflict of interest.

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52. Ward NL, Loyd CM, Wolfram JA, Diaconu D, Michaels CM, McCormick TS, Depletion of antigen-presenting cells by clodronate liposomes reverses the psoriatic skin phenotype in KC-Tie2 mice, Br J Dermatol. 164 (2011) 750-758 53. Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE, et al., c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin, CELL. 103 (2000) 745-755 54. Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D, et al., Psoriasislike skin disease and arthritis caused by inducible epidermal deletion of Jun proteins, NATURE. 437 (2005) 369-375 55. Li AG, Wang D, Feng XH, Wang XJ, Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder, EMBO J. 23 (2004) 17701781 56. Zhang Y, Meng XM, Huang XR, Wang XJ, Yang L, Lan HY, Transforming growth factor-beta1 mediates psoriasis-like lesions via a Smad3-dependent mechanism in mice, Clin Exp Pharmacol Physiol. 41(2014) 921-932 57. Koegel H, von Tobel L, Schafer M, Alberti S, Kremmer E, Mauch C, et al., Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice, J CLIN INVEST. 119 (2009) 899-910 58. Tak PP, Firestein GS, NF-kappaB: a key role in inflammatory diseases, J CLIN INVEST. 107 (2001) 7-11 59. Rebholz B, Haase I, Eckelt B, Paxian S, Flaig MJ, Ghoreschi K, et al., Crosstalk between keratinocytes and adaptive immune cells in an IkappaBalpha proteinmediated inflammatory disease of the skin, IMMUNITY. 27 (2007) 296-307 60. Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, et al., TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2, NATURE. 417 (2002) 861-866 61. Stratis A, Pasparakis M, Rupec RA, Markur D, Hartmann K, Scharffetter Kochanek K, et al., Pathogenic role for skin macrophages in a mouse model of keratinocyteinduced psoriasis-like skin inflammation, J CLIN INVEST. 116 (2006) 2094-2104 62. Andres RM, Hald A, Johansen C, Kragballe K, Iversen L, Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity, EXP DERMATOL. 22 (2013) 323-328 63. Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, et al., Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17dependent autoimmunity, J IMMUNOL. 179 (2007) 4313-4317 64. Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al., Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model, NAT MED. 11(2005) 43-49 65. Takaishi M, Ishizaki M, Suzuki K, Isobe T, Shimozato T, Sano S, Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17, J DERMATOL SCI. 85 (2017) 12-19.

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66. Johnston A, Fritz Y, Dawes SM, Diaconu D, Al-Attar PM, Guzman AM, et al., Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation, J IMMUNOL. 190 (2013) 2252-2262 67. Karbach S, Croxford AL, Oelze M, Schüler R, Minwegen D, Wegner J, et al., Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 34 (2014) 2658-2668 68. Wohn C, Brand A, van Ettinger K, Brouwers-Haspels I, Waisman A, Laman JD, et al., Gradual development of psoriatic skin lesions by constitutive low-level expression of IL-17A, CELL IMMUNOL. 308 (2016) 57-65 69. Rebecca Schüler, Anna Brand, Sabrina Klebow, Johannes Wild, Flávio Protásio Veras, Elisabeth Ullmann, et al., Clausen, Susanne Karbach Antagonization of IL- 17A attenuates skin inflammation and vascular dysfunction in mouse models of psoriasis, Nat Rev Immunol. 10 (2010) 236-47 70. Kopp T, Kieffer JD, Rot A, Strommer S, Stingl G, Kupper TS, Inflammatory skin disease in K14/p40 transgenic mice: evidence for interleukin-12-like activities of p40, J INVEST DERMATOL. 117 (2001) 618-626. 71. Cheng J, Turksen K, Yu QC, Schreiber H, Teng M, Fuchs E, Cachexia and graftvs.host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice, Genes Dev. 6 (1992)1444-1456. 72. Guo L, Yu QC, Fuchs E, Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice, EMBO J. 12 (1993) 973-986. 73. Igney FH, Asadullah K, Zollner TM, Humanised mouse models in drug discovery for skin inflammation, Expert Opin Drug Discov. 1 (2006) 53-68. 74. Wrone-Smith T, Nickoloff BJ, Dermal injection of immunocytes induces psoriasis, J CLIN INVEST. 98 (1996) 1878-1887 75. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO, Spontaneous Development of Psoriasis in a New Animal Model Shows an Essential Role for Resident T Cells and Tumor Necrosis Factor-α , The Journal of Experimental Medicine. 199 (2004) 731-736 76. Garcia M, Escamez MJ, Carretero M, Mirones I, Martinez-Santamaria L, Navarro M, Jorcano JL, Meana A, Del Rio M. Modeling normal and pathological processes through skin tissue engineering. Mol Carcinog. 46 (2007) 741-5. 77. Zeigler M, Chi Y, Tumas DB, Bodary S, Tang H, Varani J, Anti-CD11a Ameliorates Disease in the Human Psoriatic Skin-SCID Mouse Transplant Model: Comparison of Antibody to CD11a with Cyclosporin A and Clobetasol Propionate, LAB INVEST. 81 (2001) 1253-1261 78.Krueger GG, Chambers DA Shelby J. Involved and uninvolved skin from psoriatic su bjects: are they equally diseased? Assessment by skin transplanted to congenitally athymic (nude) mice, J Clin Invest. 68 (1981) 1548-57 79. Fraki JE, Briggaman RA, Lazarus GS, Uninvolved skin from psoriatic patients

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develops signs of involved psoriatic skin after being grafted onto nude mice, SCIENCE. 215 (1982) 685-687 80. Nickoloff BJ, Kunkel SL, Burdick M, Strieter RM, Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am J Pathol. 146 (1995) 580-8 81. Gilhar A, David M, Ullmann Y, Berkutski T, Kalish RS, T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice, J INVEST DERMATOL. 109 (1997) 283-288. 82. Nickoloff BJ, Wrone-Smith T, Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis, AM J PATHOL. 155 (1999) 145-158. 83. Bhagavathula N, Nerusu KC, Hanosh A, Aslam MN, Sundberg TB, Opipari AW, et al., Varani J, 7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)- 4,5dihydro-1H-benzo[1,4]diazepin-2(3H)-one (Bz-423), a Benzodiazepine, Suppresses Keratinocyte Proliferation and Has Antipsoriatic Activity in the Human Skin-Severe, Combined Immunodeficient Mouse Transplant Model, J PHARMACOL EXP THER. 324 (2007) 938-947 84. Stenderup K, Rosada C, Shanebeck K, Brady W, Van Brunt MP, King G, et al., AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use— improves psoriasis in a human xenograft transplantation model, Protein Engineering Design and Selection. 28 (2015) 467-480. 85. Zhou J, Gao Y, Yi X, Ding Y, Ginsenoside Rh2 Suppresses Neovascularization in Xenograft Psoriasis Model, CELL PHYSIOL BIOCHEM. 36 (2015) 980-987 86. Wu JK, Siller G, Strutton G: Psoriasis induced by topical imiquimod. AUSTRALAS J DERMATOL 2004, 45(1):47-50. 87. Fanti PA, Dika E, Vaccari S, Miscial C, Varotti C: Generalized psoriasis induced by topical treatment of actinic keratosis with imiquimod. INT J DERMATOL 2006, 45(12):1464-1465. 88. Van der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al., Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice Is Mediated via the IL23/IL-17 Axis, The Journal of Immunology. 182 (2009) 5836-5845 89. Jean Christopher Chamcheu1*, Vaqar M. Adhami1, Stephane Esnault2, Mario Sechi4, Imtiaz A. Siddiqui1, et al., Dual inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant Delphinidin Ameliorates Psoriatic Features In-vitro and in an Imiquimod-induced Psoriasis-like Disease in Mice, Antioxid Redox Signal. 26 (2017) 49-69 90. Liu H, Wang Y, Li W, Li C, Jiang Z, Bao J, et al., Anti-Psoriasis Effects and Mechanisms of Α -(8-Quinolinoxy) Zinc Phthalocyanine-Mediated Photodynamic Therapy, CELL PHYSIOL BIOCHEM. 44 (2018) 200-214 91. Chan JR, 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, The Journal of Experimental Medicine. 203 (2006) 2577-2587

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92. Clarke AW, Poulton L, Wai HY, Walker SA, Victor SD, Domagala T, et al., A novel class of anti-IL-12p40 antibodies: potent neutralization via inhibition of IL-12- IL12Rbeta2 and IL-23-IL-23R, MABS-AUSTIN. 2 (2010) 539-549 93. Sarra M, Caruso R, Cupi ML, Monteleone I, Stolfi C, Campione E, et al., IL-21 promotes skin recruitment of CD4 (+) cells and drives IFN-gamma-dependent epidermal hyperplasia, J IMMUNOL. 186 (2011) 5435-544

Journal Pre-proof e

Y

Y

N

N

ND

N

Y

D

Flaky

Y

Y

N

Y

Y

skin(Ttcfsn/Tt

Referenc

Y

Vasculari

Y

1 /Scd1 )

zation

Y

Cytokine

Y

ab

expression

Y

microabs

cesses

Y

Neutrop

hil

Y

T-cell

infiltration Epiderm

al

model

infiltration Acanthos

Asebia(Scd ab

Hyperke

Spontaneous

is

ratosis

Mouse

model

Human psoriasis

[26] N

Y

D

[29]

cfsn) cpdm/cpdm

Y

Y

N

Y

Y

Y

Y

CD18

engineered mouse

P

Y

Y

Y

L/J

models

K14-VEGF

Y

Y

al

KC-Tie2

Y

K5-JunB/c-

rn

Jun

Jo u

K5.TGFβ1

K5-SRF

Y

Y

Y

Y

Y

Y

Y

pr

Il1rn(−/−)

Y

Y

e-

Y

Y

Pr

TgIL1.1

Y

Y

Y

Y

oo

Genetically

f

[36] hypo

Y

Y [42]

Y

N

N

D Y

[46] N

Y

D Y

Y

[47] Y

Y [48]

Y

Y

N

Y

D Y

Y

Y

Y

[51] Y

Y [54]

Y

Y

Y

Y

N

Y

D Y

Y

Y

Y

ND

[55] Y

ND

mutant

K5-IκBα-

[57] Y

Y

Y

Y

Y

Y

Y

deficient

K14-IKK2

[59] Y

Y

Y

ND

Y

Y

ND [61]

K5.Stat3C

Y

Y

Y

Y

Y

Y

Y [64]

K5-IL-17C

Y

Y

Y

Y

Y

Y

Y [66]

K14-IL-

Y

Y

Y

Y

Y

Y

Y

17Aind/+ DC-IL-

[67] Y

Y

Y

Y

Y

Y

Y

ind

17A

K14-P40

[68] Y

N

Y

Y

ND

Y

Y

Journal Pre-proof [70] K14-TNF

Y

Y

ND

ND

ND

Y

ND [71]

K14-KGF

Y

Y

N

N

N

Y

N [72]

Xenotransplanta tion models

Athymic

Y

Y

Y

Y

Y

Y

Y

nude mouse SCID

[78] Y

Y

Y

Y

Y

Y

Y

mouse

[81]

AGR129

Y

Y

Y

Y

Y

Y

Y

mouse Y

Y

induced model Y

Y

Y

Y

Y

Y

Y

Y [88]

Y

Y

pr

IL-23-

Y

f

Y

injected

IL-21-

ND

N

Y

Pr

injected

e-

model

rn

al

model

Jo u

Models

IMQ-

oo

Direct Induction

[75]

ND

[91]

ND

Y

N [93]

Journal Pre-proof

Therapies

Cyclospor in A

Administration

The asebia mouse

subcutaneous injection

Helminth glycan LNFP III

Flaky skin mouse

subcutaneous injection

Calcipotri ene

cpdm/c pdm mouse

topical delivery

Etretinate

cpdm/c pdm mouse cpdm/c pdm mouse

intragastric administration

cpdm/c pdm mouse cpdm/c pdm mouse cpdm/c pdm mouse

intragastric administration

oo

pr

Pr

al

rn

Jo u

Corticoste roids

Dapsone

Loratidin e Capsaicin

specific pathway or aspect of the pathology against inflammatory cells infiltration, especially mast cells enhance the expression of JunB and caspase-14 reduce expression of IFN-γ and turn the CD4/CD8 ratio close to be normal reduce epidermal hyperplasia and the levels of eosinophils not very effective

Refere nce

[28]

[31]

f

topical application

n

Flaky skin mouse

e-

Delphinidi

Mouse model

topical delivery

intragastric admin istration topical delivery

[35]

[39]

[39]

reduce epidermal [39] hyperplasia and the levels of eosinophils decrease epidermis [39] thickness inhibit the pruritus [39] reduce epidermal thickness

[39]

Journal Pre-proof CD18hyp intragastric admin o PL/J istration mouse

VEGF Trap

K14VEGF mouse

subcutaneous injection

K14VEGF mouse

transdermal delivery

[44]

[48]

[49]

intradermal injection

Jo u

rn

Clodronat KCe liposome Tie2 with mouse consumption of APCS

topical delivery

Pr

K14VEGF mouse

al

HK

e-

pr

-4

oo

UCL/mIL

decrease the expression of Th17-related cytokines and phosphorylated STAT5 antagonismV EGF and eliminate hyperplastic vascular phenotype inhibit the expression of ICAM-1, VCAM-1 and E-selectin and inflamed blood vessels inhibit p38, ERK1/2 and AKT signaling pathways decrease dermal angiogenesis and returne the expression of + CD8 T cell, IL1α, IL-6, IL-23 and TNF-α to normal levels decrease the levels of TGFβ1, IL-6, IL-23, IL-17A decrease the expression of IL-17A, without affect the expression of IFN-γ

f

JAK 1/JAK3 inhibitor R348

Smad3 inhibitor SIS3

K5.TGF β1wt mouse

RORgt antagonist A213

K5.Stat 3C mouse

topical delivery

intragastric administration

[50]

[52]

[56]

[65]

Journal Pre-proof K5-IL17C mouse

injection

IL-17A neutralizing antibody (BZN035) IL-17A neutralizing antibody (BZN035)

K14-IL17Aind/+ mouse

injection

DC-IL17Aind/ind mouse

injection

Cyclospor in A

SCID mouse

intraperitoneal injection

antiCD11α

SCID mouse

intraperitoneal injection

AZ17

GRh2

Delphinidi n

oo topical delivery

SCID mouse

intraperitoneal injection

AGR12 9 mouse

subcutaneous injection

IMQinduced mouse

decrease the level of IL-6, IL22, and TNF-α and reverse vascular dysfunction reduce the epidermal thickness reduce the epidermal thickness reduce the epidermal thickness inhibit keratinocyte proliferation improve the epidermal thickness, vessel occurrence and lymphocyte infiltration decrease the level of VEGFA reduce the activation of PI3K/Akt/mTO R pathway

[69]

pr

e-

Pr

al

SCID mouse

Jo u

Bz-423

topical delivery

rn

Clobetasol SCID propionate mouse

reduce infiltration of [66] CD4+ and CD8+ T cell counts as well as the levels of IFN-γ, IL-6 and IL-1β not very effective [69]

f

TNF-a inhibition (CNTO5048 )

topical delivery

[77]

[77]

[77]

[83]

[84]

[85]

[89]

Journal Pre-proof

IL-17A neutralizing antibody (BZN035)

IMQinduced mouse

photodynamic therapy

injection

e-

Pr

intraperitoneal injection

al

intragastric administration

rn

RORgt antagonist A213

IL-23induced mouse IL-23induced mouse

Jo u

AZ17

intraperitoneal injection

[90]

[69]

[92]

pr

Anti-ILIL-2312p40 induced antibody(h6f mouse 6)

decrease the levels of PCNA, Bcl-2 increased the level of Bax decrease the infiltration of myeloid cells, neutrophils, macrophages and the levels of IL-6, IL-22 and IL-1β inhibit the infl ammatory response and reduce epidermal hyperplasia inhibit the ear inflammation reduce the percentage of Th17 cells and CD4+ T cells and levels of IL17A, IL-22

f

IMQinduced mouse

oo

ZnPc-F7PDT

[84]

[65]

Journal Pre-proof

Jo u

rn

al

Pr

e-

pr

oo

f

There is no conflict of interest between the authors

Figure 1