Keratin 17: a Critical Player in the Pathogenesis of Psoriasis

Keratin 17: A Critical Player in the Pathogenesis of Psoriasis

Liang Jin and Gang Wang

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China

Published online 30 May 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21291 ᭢

Abstract: Keratin 17 (K17) is an intermediate filament protein present in the basal cells of complex epithelia, such as nails, hair follicles, sebaceous glands, and eccrine sweat glands. Studies have shown that it is expressed aberrantly in the suprabasal keratinocytes of psoriatic lesions, compared to in normal epidermis. K17 is also closely associated with the immune system and plays an important role in the pathogenesis of psoriasis. In this review, we present our experimental findings concerning the role of K17 in psoriasis, and compare them to results published in the literature. Our results show that cytokines related to Th17 and IL-22-producing (where Th17 is T helper cells, type 17 and IL is interleukin) CD4+ T cells, including IL-17A and IL-22, upregulate the expression of K17 in keratinocytes. In addition, K17 stimulates autoreactive T cells and promotes the production of psoriasis-associated cytokines. Our findings lend support to the hypothesis that a K17/T-cell/cytokine autoimmune loop is involved in the pathogenesis of psoriasis. We therefore review the current understanding of the K17 immunoregulation, including its expression and direct/indirect effects on immune responses. Pertinent strategies for the treatment of psoriasis are also discussed. C 2013 Wiley Periodicals, Inc. Med. Res. Rev., 34, No. 2, 438–454, 2014

Key words: keratin 17; psoriasis; immunoregulation; keratinocytes; positive feedback loop

1. INTRODUCTION

A. Psoriasis

Psoriasis is a common chronic T-cell-mediated skin disease characterized by inﬂammation, hyperproliferation, aberrant differentiation of keratinocytes, and high relapse rate.1 The overall prevalence of this condition is 2–3% worldwide, higher in American and Canadian populations (4.6–4.7%) than in African and Asian populations (0.4–0.7%).2, 3 Physical manifestations of psoriasis include the presence of raised, well-demarcated, scaly, erythematous oval plaques. Histological manifestations include parakeratosis, acanthosis, and telangiectasis,4 contributing to adherent scales, raised plaques, and erythematous plaques, respectively (Fig. 1A). Clinically,

Correspondence to: Gang Wang, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an 710032, China. E-mail: [email protected].

Medicinal Research Reviews, 34, No. 2, 438–454, 2014 C 2013 Wiley Periodicals, Inc. KERATIN 17 r 439

Figure 1. (A) Clinical and dermatopathological manifestations of psoriasis. (a) Raised plaques, (b) adherent scales, (c) erythematous plaques, (a) acanthosis, (b) parakeratosis, (c) telangiectasis. (B) Classification of psoriasis. (1) Psoriasis vulgaris, (2) guttate psoriasis, (3) erythrodermic psoriasis, (4) pustular psoriasis, (5) palmoplantar pustulosis, (6) scalp psoriasis, (7) inverse psoriasis, (8) nail psoriasis, and (9) psoriatic arthritis. All images reproduced courtesy of the Department of Dermatology at Xijing Hospital of Fourth Military Medical University. psoriasis is classified into psoriasis vulgaris (plaque psoriasis; Fig. 1B-1), guttate psoriasis (Fig. 1B-2), erythrodermic psoriasis (Fig. 1B-3), pustular psoriasis, either generalized (Fig. 1B-4) or palmoplantar pustulosis (Fig. 1B-5), psoriasis on specific locations, including scalp psoriasis (Fig. 1B-6), flexural psoriasis (Fig. 1B-7), and nail psoriasis (Fig. 1B-8), and psoriatic arthritis (Fig. 1B-9) as well.5 As a T-cell-mediated inflammatory skin disease, psoriasis outbreaks due to multiple envi- ronmental and genetic factors. Classical genome-wide linkage analysis has identified a psoriatic locus psoriasis susceptibility 1 (PSORS1) on chromosome 6p21.3 in human as the major genetic determinant. Within the locus, polymorphisms of the genes for HLA-C (where HLA is human leukocyte antigen), coiled-coil α helical rod protein 1 (CCHCR1), and corneodesmosin (CDSN) are closely associated to the incidence of psoriasis.6 With the advent of genome-wide association study, more single nucleotide polymorphisms (SNPs), such as IL-23R (where IL is interleukin), IL-12B, late cornified envelope (LCE), HLA-Cw*-0602, zinc-finger protein 313 (ZNF313), and tumor necrosis factor α induced protein 3 (TNFAIP3), have been identified in psoriasis-associated genes than before.7 Detailed information regarding these genetic factors is available in a review published by Roberson et al.7 in 2010. The development of psoriasis is mainly mediated by Th1, Th17, and IL-22-producing CD4+ T cells (where Th1 is T helper cells, type 1 and Th17 is T helper cells, type 17).8 A proposed pathogenic mechanism for psoriasis suggests that keratinocytes in susceptible individuals, in the face of stressful stimuli, such as oxidative stress, infection by microorganisms, drugs, trauma, and smoking, may secrete antimicrobial peptide.a The antimicrobial peptide and DNA released by the dying cells form the complexes that activate plasmacytoid dendritic cells (pDCs) in the dermis.9 These pDCs produce IFN-α (where IFN is interferon) which may activate myeloid dendritic cells (mDCs). In turn, these mDCs induce the differentiation of Th1, Th17, and IL-22-producing CD4+ T cells in regional lymph nodes,10 and then these T cells move back into the dermis where

aAntimicrobial peptides, an evolutionarily conserved component of the innate immune response, are small molecular weight proteins with broad-spectrum antimicrobial activity against bacteria, viruses, and fungi. Various epithelia including skin could produce antimicrobial peptides, some of which are expressed by keratinocytes in skin.

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Figure 2. (A) The homology analysis of K17 amino acid sequence. Keratin 17 (K17) comprises head, rod, and tail domains and is highly homologous among human, murine, and bovine versions. Hu, Human. (B) A schematic representation of the K17 peptide epitopes. Peptide epitope S1 and S3 share the “ALEEANxxL” and “GLRRxLD” sequence with streptococcal M6 protein. Peptide epitope S1, S2, S4–1, and S4–2 of K17 induce psoriatic T-cell proliferation and IFN-γ (where IFN is interferon) production speciﬁcally.13 *The stimulation of S3 was proved by Johnston et al.58 they produce large amounts of cytokines, including TNF-α (where TNF is tumor necrosis factor), IFN-γ , IL-17, and IL-22. These cytokines activate the keratinocytes and promote their proliferation and production of chemokines, resulting in the recruitment of more immune cells into the lesion.6 An important characteristic of activated keratinocytes is the altered expression from K1 and K10 to K6, K16, and K17.2 Among them, K17 plays a pivotal role in the pathogenesis of psoriasis.11–13

B. K17

Keratins are a family of fibrous structural proteins, including 28 type I (acidic) and 26 type II (basic) members.14 Keratins assemble into heteropolymers, that is, a type I and a type II protein form a heterodimer. Each keratin pair is characteristic of a particular epithelial differentiation program. For instance, in normal epidermis, basal keratinocytes express K5 (type II)/K14 (type I), whereas suprabasal cells express K1 (type II)/K10 (type I).14 Keratins are multifunctional proteins in which missense mutations may result in a broad range of tissue-specific diseases.15 In addition to providing mechanical support to cells, there is growing evidence that they are associated with, not only proliferation and differentiation, but also apoptosis, epithelial wound healing, tissue polarity, and epithelial remodeling.16, 17 K17 belongs to the group of human type I (acidic) epithelial keratins that provide mechanical support to keratinocytes to maintain the integrity of the epidermis.18, 19 To function as a mechanical support, K17 heterodimerize with K6b (type II) into keratin heteropolymers and intermediate filaments network attached to desmosomes at points of cell–cell contacts.16 K17 is also an important marker for the proliferation of human epithelial cells20 (see details at

Medicinal Research Reviews DOI 10.1002/med KERATIN 17 r 441 the Human Intermediate Filament Database,14 http://www.interfil.org/index.php). This keratin is a 432 amino acid tripartite structure composed by three domains: head, rod, and tail (Fig. 2A).21 Human and mouse orthologous K17 amino acid sequences are 88% alike in the head domain, 96% alike in the rod domain, and 97% alike in the tail domain.22 In the human and bovine orthologous K17s, the amino acid sequences are also similar in the rod and tail domains, with homologies of 95% and 93%, respectively (Fig. 2A). This high degree of homology in the amino acid sequences of the rod and tail domains suggests that K17 is a highly conserved protein and may be indispensable for some basic cellular functions mentioned in the following text. K17 is mainly expressed in the basal cells of complex epithelia, such as in finger nails, hair follicles, sebaceous glands, and eccrine sweat glands.23, 24 More specifically, it is located in the apex of the matrix and nail bed epithelium.25 In hair follicles and sebaceous glands, K17 is situated suprabasally in the epidermis of the lower part of the infundibulum, sebaceous duct, and the outer root sheath below the opening of the sebaceous ducts.24 In eccrine sweat glands, it is expressed in the luminal cells of the acrosyringium and intradermal ducts as well as in the myoepithelial cells of the secretory portion of the glands.26 In 2004, Tong et al.27 found a specific functional K17n (n stands for nail) in the epidermis of the nail in mice. However, the existence of human ortholog still needs to be confirmed. As a member of the keratin family, K17 is also multifunctional. McGowan et al.22 observed that K17-expressing cells give rise to placodes, the precursors of ectoderm-derived appendages (hair, glands, and teeth), and to the periderm during mouse skin development, which suggests that K17 is involved in the differentiation and development of epithelial appendages. Clinically, K17 mutations result in steatocystoma multiplex and pachyonychia congenita type II autosomal dominant inherited appendage-related disorders.15, 28, 29 McGowan et al.30 described that K17 null mice exhibited severe alopecia during the first week after birth due to the sequestering of TNF receptor 1-associated death domain protein by K17 in the cytoplasm. This results in negative modulation of TNF-α function and apoptosis.31 The data have shown that K17 normally promotes hair follicle growth by attenuating the pro-apoptotic influence of TNF-α. Another role of K17 is in epidermal wound healing through binding with 14–3–3 proteins. This action increases the cytoplasmic levels of these proteins, resulting in the activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)b signaling and the upregulation of the protein synthesis rate.32 In addition, K17 has an immune-modulation function. Hughes et al.33 found that K17 is significantly expressed in acne, a Th1-shifted inflammatory skin disease with increased IFN-γ , which suggests that K17 may be associated with Th1-type immune responses.34 Depianto and co-workers found that K17 promoted basaloid skin tumor growth by enhancing Th1-type immune responses.35 Research has shown that under some stressful conditions, such as viral infection, injury, tumor growth, and psoriasis, the expression of K17 is obviously upregulated, suggesting that it is closely associated with the response to stress.36–40 Our group has focused on investigating the correlation between K17 and the pathogenesis of psoriasis. Our previous studies41 have demonstrated that a K17/T-cell/cytokine autoimmune loop is involved in the psoriatic pathogenesis. In this review, we summarize the current understanding of K17 with regard to the pathogenesis of psoriasis and K17-related therapeutic strategies. Areas of potential breakthroughs in this field, such as upstream regulatory factors and downstream cytokines, such as IFN-γ , IL-17A, and IL-22, are discussed as well.

bPI3K/Akt/mTOR pathway is an intracellular signaling pathway important in cell proliferation, cell motility, apoptosis, protein synthesis, and transcription. PI3K activates Akt, a serine/threonine protein kinase, which activates mTOR, another serine/threonine protein kinase.

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2. K17 AND PSORIASIS

A. Expression of K17 in Psoriasis

In the 1990s, Wilson et al.11 observed that K17 was expressed in the epidermis of psoriatic scalp; which was the first indication that K17 may be associated with this condition. In the following year, de Jong et al.42 compared the K17 expression in the epidermis of psoriatic lesions, before and after treatment in six psoriatic patients. Their results showed that K17 expression levels were positively associated with psoriasis severity, suggesting a role in the psoriatic pathogenesis. In 1995, Leigh et al.43 confirmed that K17, a marker of keratinocyte hyperproliferation in psoriasis, was present in suprabasal psoriatic epidermis in vivo and in vitro. These results indicated a correlation between K17 and psoriasis, giving rise to further research. As it is known, “epidermal differentiation” is a program keratinocytes go through when they move upward to suprabasal layers after their proliferation in the basal layer. “Epidermal terminal differentiation” refers to the final step of this differentiation program in which keratinocytes convert from living cells into corneocytes. In psoriatic lesions, the growth of keratinocytes is increased and terminal differentiation is inhibited. In 1991, Thewes et al.44 found that the expression of K14 was elevated while expression of K1 and K10 was decreased in the suprabasal cells. In addition, the cells in the upper spinous and granular layers were induced to express the proliferation-related keratins K6, K16, and K17 in psoriatic lesions, whereas K5 and K14 were downregulated, suggesting the possibility that the K17 gene upregulation compensated for the downregulation of other keratin genes, such as K5 or K14 gene in psoriasis. The following sections describe additional evidence linking K17 to psoriasis.

B. K17 and Psoriasis-Associated Cytokines

Psoriasis-related cytokines IFN-γ , IL-17A, and IL-22 are known to upregulate K17 expression.45–47 As mentioned above, T helper cells, such as, Th1, Th17, and IL-22-producing CD4+ T cells, contribute to the pathogenesis of psoriasis through the release of inflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation, and sustained inflammation.48 Key inflammatory cytokines in this response are IFN-γ , IL-17A, and IL-22. In psoriasis, overexpression of these proinflammatory cytokines can induce psoriatic lesions, and vice versa, which suggests that they play an important role in the pathogenesis of the disease.49–52 Although K6 and K16 are also overexpressed in the hyperproliferative psoriatic epidermis, K17 is the only known keratin induced by these psoriasis-associated cytokines.46 In 1992, Flohr et al.53 discovered that IFN-γ , a Th1 cytokine, upregulated the expression of a novel keratin class I gene that encodes a 432 amino acid protein in the HeLa cell line. In the same year, Troyanovsky et al.54 examined the characteristics of this K17 by using a cDNA cloned from a HeLa cDNA library, finding that the K17 gene contained eight exons and seven introns and encoded a 432 amino acid polypeptide with a calculated molecular weight of 48,000. Jiang et al.55 later confirmed that IFN-γ upregulated K17 gene expression by activating the transcription factor, STAT1 (where STAT is signal transducer and activator of transcription), in human keratinocytes. They also analyzed the molecular basis of this upregulation and identified the IFN-γ activation site in the promoter region of the K17 gene. Bonnekoh et al.45 and Vogel et al.56 confirmed these results in an immortal human adult skin keratinocytes replicating under low Ca2+ and elevated temperature condition (HaCaT) cell line. They also hypothesized that the aberrant K17 gene expression observed in psoriatic lesions may be a consequence of IFN-γ overexpression and described K17 as a psoriasis-associated cytokeratin. On the basis of the above results, Komine et al.57 continued the study of K17 regulation, showing that cytokines, such as IL-6 and leukemia inhibitory factor, are able to induce the

Medicinal Research Reviews DOI 10.1002/med KERATIN 17 r 443 phosphorylation of STAT1 and could also induce the transcription of the K17 gene. However, they found that IL-3, IL-4, IL-10, IFN-α,IFN-β, and granulocyte macrophage colony stimu- lating factor, which do not induce phosphorylation of STAT1, had no effect on K17 expression. They also demonstrated that the regulatory mechanism of K17 was operative in psoriasis, which is associated with higher levels of IFN-γ than in atopic dermatitis. In 1999, Wei et al.58 observed IFN-γ -induced K17 expression completely through endogenous IL-1 production by using a skin organ culture model. In vitro, however, IL-1 was not able to induce K17 expression in the HaCaT cell line. The fact that IL-1 did not equally induce K17 expression in the two conditions may be attributed to different keratinocyte responses in vivo and in vitro. This also suggests a complex regulatory mechanism of K17 expression in psoriasis. In 2011, our group46 showed that IL-17A, another psoriasis-associated cytokine, could also upregulate K17 expression on the transcriptional and translational level in both the HaCaT cell line and primary human keratinocytes via STAT1/3 signaling pathways. On the mouse ear, we found that K17 expression was increased in epidermis after IL-17A injection into the skin. However, it remains to be investigated whether this regulation is dependent on IL-1. Recently, we found that IL-22 could also upregulate the K17 expression via the STAT 3 and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways.47 This suggests that ERK1/2 signals are also involved in the expression of K17. Up to date, IFN-γ , IL-17A, and IL-22 (Th1 and Th17 cell cytokines) have been found to induce K17 expression, whereas IL-4 and IL-10 (Th2 cytokines) do not. This is consistent with the main immune cells found in psoriasis because Th1, Th17, and IL-22-producing CD4+ T cells, along with the upregulation of K17, induced by IFN-γ , IL-17A, and IL-22, play a dominant role in the pathogenesis of psoriasis. Therefore, K17 is clearly a major link between psoriasis-associated cytokines and psoriatic phenotypes.

C. K17 and Autoreactive T Cells in Psoriasis

In the pathogenesis of psoriasis, K17 is a major target antigen recognized by autoreactive T cells because it shares similar epitopes with streptococci and promotes the proliferation and cytokines secretion of T cells.13, 59, 60 As stated earlier, psoriasis can be clinically classified into several types. Among them, guttate psoriasis is characterized by the formation of smaller psoriatic papules roughly 2 weeks after a throat infection. Tervaert et al.61 isolated streptococci from the throat of 97% of patients with guttate psoriasis; Leung et al.62 found that V beta 2+ T cells in acute guttate skin lesions could be activated by streptococcal superantigens. Davison et al.63 further confirmed that V beta-restricted CLA+ (where CLA is cutaneous lymphocyte-associated antigen) skin homing lymphocytes, activated by streptococcal superantigens, contributed to guttate psoriasis. Psoriasis vulgaris is the most common type of psoriasis, accounting for approximately 90% of cases.64 It is also closely associated with hemolytic streptococci infections. Gudjonsson et al.65 found that 29.3% of patients with this type of psoriasis had sore throats, compared with only 2.6% infection in control subjects, and that infection with group A β-hemolytic streptococci was 10.6-fold higher in these patients than in healthy controls. Moreover, epidemiological ob- servations indicated that streptococcal throat infections exacerbated chronic psoriasis vulgaris. In short, these results suggest that streptococcal throat infection is a prime cause of psoriasis, especially the guttate form, and that streptococcal superantigens appear to play a vital role in psoriatic pathogenesis. Several virulent factors, including M-protein, hemolysins, and extracellular enzymes, contribute to group A β-hemolytic streptococcal infections. Among them, M-protein, a primary virulence, resists opsonization and inhibits the activation of the complement by binding to the C4b-binding protein and fibrinogen. At the same time, the infected body could gener- ate antibodies against M-proteins, which helps in the destruction of the microorganism.66

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M-protein is also a major superantigen in psoriasis.67 In 1999, Gudmundsdottir et al.59 found that a K17-derived peptide sharing the “ALEEANxxL” amino acid sequence with M-proteins induced T cells to produce IFN-γ in psoriatic patients. This indicates that K17 may be a major target for autoreactive T lymphocytes in psoriasis. In 2004, Johnston et al.60 found that K17 shares not only the “ALEEANxxL” but also the “GLRRxLD” sequence with M-proteins (Fig. 2B). Therefore, during the pathogenesis of psoriasis, especially guttate psoriasis, when pre- disposed HLA-Cw*0602+ patients contract a throat infection induced by group A β-hemolytic streptococci, T cells become primed to the M-protein within the pharyngeal tonsils, thereby inducing skin-homing characteristics with an increase in CLA expression, which is known to be a specific homing receptor that facilitates T-cell recruitment into the skin.68 These cells then migrate from the tonsil into the epidermis where they recognize the “ALEEANxxL” or “GLRRxLD” sequence of K17, which is presented by antigen-presenting cells (APCs) or activated keratinocytes, and then secret IFN-γ , a Th1-type cytokine. These immune cells and cytokines eventually contribute to the formation of psoriatic plaques. In 2004, our group cloned and expressed anti-K17 human monoclonal antibodies by pan- ning a semisynthetic phage antibody library against human epidermal keratins extracted from psoriatic scales.69 In the following year, we discovered three new immunodominant T-cell activating epitopes on K17 in addition to the “ALEEANxxL” amino acid sequence (Fig. 2B).13 However, we did not confirm the stimulatory activity of the K17 “GLRRxLD” sequence on T-cell proliferation and IFN-γ production in psoriasis. It is highly possible that some other molecules that share immunogenic characteristics with K17 could also be involved in the disease. The known example is M-protein, which has the “ALEEANxxL” sequence. Exogenous or endogenous proteins, which share three new immunodominant T-cell activating epitopes on K17, might also be involved in the psoriatic process. This hypothesis deserves validation in the future, although it’s still unknown that these new epitopes are shared by which molecules. In another study, we found that K17-specific analogs of peptides with T-cell receptor con- tact residue substitutions (altered peptide ligands) were able to inhibit T-cell proliferation and secretion of Th1-type cytokines in psoriasis.41 This finding confirmed that T-cell activating epitopes do indeed exist on K17. Psoriatic keratinocytes, if stimulated by inflammation, could rupture and release K17 protein. Then, K17 could be presented by professional APCs to T cells (Fig. 3A). Another pathway could exist, as Fan et al.70 reported that activated keratinocytes produce proinflammatory cytokines, and express both MHC (where MHC is major histocompatibility complex) class II molecules and the intercellular adhesion molecule-1; therefore, could function as the primary APCs. We hypothesize that activated keratinocytes transform into induced APCs in psoriatic lesions and present K17 to T cells by themselves (Fig. 3B). Therefore, K17 contains the antigen epitopes targeted by psoriatic autoreactive T cells; therefore, promotes the development of psoriasis.

D. K17 and Autoimmune Positive Feedback Loops in Psoriasis

K17 plays an important role in the autoimmune positive feedback loops associated with psoriasis. In psoriatic dermis, a dense inﬂammatory inﬁltrate composed of DCs, CD4+ T helper cells, and CD8+ T cells can be observed. During DCs’ activation and maturation in local tissues, immature DCs capture the antigens whose internalization can subsequently trigger their maturation and migration to lymphoid organs; then mature DCs present antigens to activate both CD4+ and CD8+ T cells.71 DCs, including mDCs and pDCs, have been validated as primary contributors to the pathogenesis of psoriasis.72 Cathelicidin (LL-37) is a type of antimicrobial peptide mainly secreted by psoriatic keratinocytes.73 Lande et al.74 showed that LL-37 broke the innate tolerance of pDCs to DNA by forming LL-37–DNA complexes that induced pDC

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Figure 3. A schematic representation of the Keratin 17 (K17)/T-cell/cytokine autoimmune positive feedback loop. IFN-γ (where IFN is interferon), IL-17A (where IL is interleukin), and IL-22 bind to their respective cell membrane bound receptors in the activated keratinocytes of psoriatic lesions and activate JAK (where JAK is Janus kinase) or the Ras/Raf/MEK (where MEK is mitogen-activated protein/extracellular signal-regulated kinase kinase) pathway leading to STAT1/3 activation and K17 gene expression. Under stress, keratinocytes are damaged or activated, and K17 is recognized and presented by dendritic cells (DCs) (A) or activated keratinocytes (B). The activated DCs or keratinocytes contain the epitopes of K17 and induce T-cell proliferation and IFN-γ , IL-17A, and IL-22 production. These cytokines act on the activated keratinocytes again and upregulate K17 gene expression. These constitute a K17/T-cell/cytokine autoimmune loop. In addition, in activated keratinocytes, we hypothesize that large amounts of K17 would bind with the 14–3–3 protein in the cytoplasm, thereby promoting the activity of mTOR and ultimately upregulating the expression of specific chemokines (C). The chemokines would recruit more T cells, which would secrete increasing amounts of psoriasis-associated cytokines. K17 gene expression would be upregulated again, and immunomodulation would be further enhanced. These steps constitute a new K17/chemokine/T-cell/cytokine autoimmune loop. activation and type I IFN production, which activate mDCs in the dermis. In addition, Ganguly et al.75 found that these complexes triggered the activation of pDCs and mDCs, leading to the production of TNF-α and IL-6, and helping mDCs differentiate into mature DCs. Mature DCs present antigens and secrete mediators inducing the differentiation of naive T cells into effector cells, Th1 and Th17, in regional lymph nodes. Similarly, K17 with its immunodominant T-cell activating epitopes might be recognized by keratinocytes and/or DCs and presented to Th cells and CD8+ T cells in psoriasis.13, 60 Therefore, K17 may initiate a pathogenic crosstalk between stressed keratinocytes and recruited DCs by inducing pDC activation and mDC maturation. Activated DCs and their cytokines play a vital role in the initiation, maintenance, and amplification of Th cell responses in psoriasis. Zaba et al.76 showed that DCs obtained from psoriatic lesions, but not from normal skin, induce T cells to produce both IL-17 and IFN-γ . Increasing evidence shows that psoriasis is a T-cell dominant immune disorder.77–79 Abnormal T-cell responses in skin, including those of CD8+ T cells, CD4+ T cells, and natural killer T cells (NKT cells), contribute to the pathogenesis.80–82 Among these cells, Th1, Th17, and IL-22-producing CD4+ T cells are found in the dermal infiltrate of psoriatic lesions to different extents, depending on the stage of disease development.83 They present different pathogenic functions by secreting specific cytokines that contribute to corresponding psoriatic phenotypes, for example, IFN-γ /TNF-α in the case of Th1, IL-23/IL-17A in Th17, and IL-22 in IL-22- producing CD4+ T cells.2

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The function of these cytokines is pleiotropic.52, 84–86 First, in psoriasis they induce keratinocytes to alter the keratinization processes including K17 expression. Second, they upregulate the expression of chemokines and adherence factors, such as those resulting in the recruitment of increasing immune cells into the epidermis and dermis; thereby ultimately deter- mining the appearance of the psoriatic phenotypes. Last, these cytokines cause immune cells to produce other speciﬁc cytokines that enhance the Th1, Th17, or IL-22-producing CD4+ T-cell pathways. These three interactions have a cascade effect initiating a serial of downstream events contributing to the development of psoriasis. During the process, cytokines, immune cells, and keratinocytes establish a positive feedback loop (Fig. 3). Keratinocytes are important links in this feedback loop. K17, as a psoriasis-associated cytokeratin, connects cytokines with T cells. Its expression was found as induced by IFN-γ in psoriasis.45 Wehave shown that K17 is able to stimulate T cells in psoriasis, as measured by cell proliferation and IFN-γ production assay.13 This constitutes a K17/T-cell/IFN-γ autoimmune loop. In addition, IFN-γ stimulates DCs to produce IL-1 and IL-23, which are thought to play a critical role in the terminal differentiation, maintenance, and pathogenicity of Th17 and IL-22-producing CD4+ T cells.75, 87–89 Moreover, we proved that IL-17A and IL-22 upregulate K17 expression in keratinocytes through the STAT1/3 or ERK1/2 signaling pathways.46, 47 Therefore, the K17/T-cell/IFN-γ /DC/IL-17A or the K17/T-cell/IFN-γ /DC/IL-22 autoimmune positive feedback loop also exists for psoriatic skin and may contribute to the maintenance and recurrence of the disease (Fig. 3).

3. K17 AND TREATMENT OF PSORIASIS

A. Treatments of Psoriasis

Common treatment options for psoriasis include topical ointments, systemic medicines (i.e., oral drugs), physical therapies, and biological therapies. Major topical ointments include corticosteroids, calcipotriol (a vitamin D analog), tazarotene (a topical retinoid), tacrolimus (a calcineurin inhibitor), and anthralin. Principal systemic medicines include methotrexate (an antimetabolite drug), cyclosporine (an immunosuppressant), oral retinoids (vitamin-A deriva- tives), and dimethylfumarate. Recently, biological therapies have become increasingly popular with the advent of research focused on the psoriatic pathogenesis. Five biologic agents are currently approved by the US Food and Drug Administration (FDA) for psoriasis treatment: alefacept (an anti-CD2 human fusion protein), adalimumab (a fully human anti-TNF-α monoclonal antibody), etanercept (a recombinant human TNF-α receptor protein fused with the Fc portion of antibodies that binds to TNF-α), inﬂiximab (a chimeric antibody that binds to TNF-α), and ustekinumab (an anti-IL12/23 IgG1 κ human monoclonal antibody). Detailed information regarding the treatment of psoriasis is available from the “Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis” published in The Journal of the American Academy of Dermatology.90–93

B. K17 in the Treatments of Psoriasis

Among the topical ointments for psoriasis, both corticosteroids and retinoids have been reported to directly repress K17 expression in keratinocytes at the transcriptional level, which is believed to be one of their action mechanisms.94–96 Anthralin was a mainstay for the topical treatment of psoriasis, which further supports our idea that K17 might be an important factor in the psoriasis.97 However its side effects raise the need for substitutions, and strategies speciﬁcally targeting K17 might be an admissible choice.90 Tacrolimus, another effective topical therapy

Medicinal Research Reviews DOI 10.1002/med KERATIN 17 r 447 for psoriasis, is used to treat the face, genitalia, and intertriginous areas. Tu et al.98 observed that tacrolimus inhibited the expression of phosphorylated STAT1 in keratinocytes induced by IFN-γ . As previously mentioned, IFN-γ induces K17 expression through the STAT1 pathway. Therefore, we hypothesize that tacrolimus can downregulate K17 expression in keratinocytes, which may contribute to its efficacy as a topical treatment for psoriasis. Among the systemic medicines for psoriasis, dimethylfumarate has been shown to inhibit IFN-γ -induced expression of K17 in the HaCaT cell line.97 In addition, Takei-Taniguchi et al.99 found that cyclosporine A inhibited the IL-17A signaling pathway in keratinocytes, which triggers K17 expression. Therefore, K17 expression might be inhibited by cyclosporine A in the treatment of psoriasis. Recently, we found that calcipotriene in a topical ointment has a similar mechanism of action, in which the downregulation of K17 is vital for its effect (unpublished data). Obviously many psoriasis medicines can downregulate K17 expression during treatment, which suggests that K17 is critical to the pathogenesis of psoriasis and is a potential therapy target. As we previously mentioned, the high levels of expression of K17 in psoriatic lesions contribute to local abnormal immune reactions by forming a K17/T-cell/cytokine autoimmune positive feedback loop. If expression of K17 could be blocked, the feedback loop will be interrupted, allowing disease regression. We have investigated anti-psoriatic therapies that target K17 in cultured normal keratinocytes and in a SCID-hu (where SCID is severe combined immunodeficiency) xenogeneic transplantation model for psoriasis.c In vitro studies showed that downregulation of K17 expression inhibited growth and induced apoptosis in keratinocytes, which was consistent with early reported functions of K17. Moreover, in this mouse model, downregulation of K17 expression in the psoriatic epidermis of xenogeneic grafts resulted in an improvement in symptoms, as measured by disease parameters, including epidermal thickness, the number of inflammatory cells, and parakeratosis.100 Anti-K17 therapies have been shown to effectively contribute to the amelioration of psoriatic symptoms, including elimination of erythema and scales, reduction of epidermal hyperplasia, acanthosis, and inflammatory cell infiltration.100 Such therapies hold tremendous potential for the future treatment of psoriasis. In addition, some medications currently used in the treatment of psoriasis may also inhibit K17 expression in keratinocytes, which support the notion that developing anti-K17 therapies may become an effective treatment option for psoriasis.

4. FUTURE PERSPECTIVES AND CONCLUSIONS

Regarding the regulation of K17 expression in psoriasis, the STAT1/3 binding sequences in the promoter region of the K17 gene have been identified. However, Milisavljevic et al.101 systematically investigated the promoter region of the human K17 gene and found eight protein binding sites. Of them, five were binding sites for known transcription factors nuclear factor 1 (NF1), activating protein 2 (AP2), and specificity protein 1 (Sp1), and three were binding sites for as-yet unidentified proteins. The currently unknown aspects of the K17 transcriptional regulation in skin inflammation require further investigations because they relate to the progress of psoriasis. This would also shed light on the function of K17 in other chronic inflammation in the epidermis or the skin as a whole. In addition to transcriptional regulation, translational and posttranslational regulation of K17 has also been reported. Pan et al.38 found that K17-Ser44 was phosphorylated in the stressed keratinocytes, contributing to increased protein synthesis

cThe SCID-hu xenogeneic transplantation model for psoriasis is a mouse model constructed by transplanting full- thickness skin xenografts from psoriatic lesions onto the backs of SCID mice and intradermally injecting peripheral blood mononuclear cells (PBMCs), which were isolated from the same donor. This model allows screening of anti- psoriatic drugs and the investigation of the pathogenesis of psoriasis

Medicinal Research Reviews DOI 10.1002/med 448 r JIN AND WANG and cell growth. Since stress in keratinocytes is also a major trigger of psoriasis, the role of K17 phosphorylation in the psoriatic pathogenesis should be further investigated. In conclusion, the psoriasis-associated cytokines (IFN-γ , IL-17A, and IL-22) can induce K17 expression in keratinocytes. In addition, K17 contains several speciﬁc psoriasis T-cell activating epitopes and is able to activate autoreactive T cells. These psoriatic T cells further upregulate local K17 expression through the production of IFN-γ , IL-17A, and IL-22. This K17-related positive feedback loop contributes to the development of psoriasis. We propose that a new autoimmune positive feedback loop (K17/chemokine/T-cell/cytokine) exists in the pathogenesis of psoriasis (Fig. 3C). Correlated studies underway in our laboratory will hopefully enhance the understanding of the K17-associated pathogenesis of psoriasis. Future studies will provide a better understanding on the regulation and functions of K17, enabling the development of new strategies modulating K17 expression in the treatment for psoriasis.

5. ABBREVIATIONS

AKT/PKB = protein kinase B AP2 = activating protein 2 APC = antigen-presenting cells CCHCR1 = coiled-coil α helical rod protein 1 CDSN = corneodesmosin CLA = cutaneous lymphocyte-associated antigen ERK1/2 = extracellular signal-regulated kinase 1/2 HaCaT = an immortal human adult skin keratinocytes replicating under low Ca2+ and elevated temperature condition HLA = human leukocyte antigen IFN = interferon IL = interleukin K = stands for “keratin” in terms keratin 1, keratin 5, keratin 6, keratin 10, keratin 14, keratin 16, and keratin 17 LCE = late cornified envelope LL-37 = cathelicidin mDCs = myeloid dendritic cells mTOR = mammalian target of rapamycin NF1 = nuclear factor 1 NKT cells = natural killer T cells PBMCs = peripheral blood mononuclear cells pDCs = plasmacytoid dendritic cells PI3K = phosphoinositide 3-kinase PSORS1 = psoriasis susceptibility 1 SCID = severe combined immunodeficiency SNP = single nucleotide polymorphism Sp1 = specificity protein 1 STAT = signal transducer and activator of transcription Th1 = T helper cells, type 1 Th17 = T helper cells, type 17 TNF = tumor necrosis factor TNFAIP3 = tumor necrosis factor α induced protein 3 ZNF313 = zinc-finger protein 313

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ACKNOWLEDGMENTS

The authors are grateful to Dr. Xiaowei Shi, Dr. Zhu Shen, Dr. Ting Chang, Dr. Wei Zhang, and Dr, Erle Dang for their contributions to the research. We thank Guodong Yang (Department of Biochemistry and Molecular Biology, FMMU) for critical review of the manuscript and Pauline Pei (Department of Dermatology, FMMU) for language editing and polishing. This work was supported by the National Natural Science Foundation of China (no. 81171494 and 81220108016, G.W.).

CONFLICT OF INTEREST

The authors declare no conﬂict of interest.

REFERENCES

1. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis—Part I: Clinical and pathologic concepts. J Allergy Clin Immunol 2011;127(5):1110–1118. 2. Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol 2012;7:385–422. 3. Christophers E. Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol 2001;26(4):314– 320. 4. McKee PH, Calonje E, Granter SR. Pathology of the Skin : With Clinical Correlations. Philadelphia: Elsevier Mosby; 2005. 195 p. 5. Bolognia J, Jorizzo JL, Schaffer JV. Dermatology. New York: Saunders; 2012. 153 p. 6. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361(5):496–509. 7. Roberson ED, Bowcock AM. Psoriasis genetics: Breaking the barrier. Trends Genet 2010;26(9):415– 423. 8. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis—Part II: Immune cell subsets and therapeutic concepts. J Allergy Clin Immunol 2011;127(6):1420–1432. 9. Gilliet M, Lande R. Antimicrobial peptides and self-DNA in autoimmune skin inﬂammation. Curr Opin Immunol 2008;20(4):401–407. 10. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol 2009;9(10):679–691. 11. Wilson CL, Deane D, Wojnarowska F, Lane EB, Leigh IM. Follicular keratin expression in normal and psoriatic scalp (abstr). J Invest Dermatol 1990;95:495. 12. Bockelmann R, Horn T, Gollnick H, Bonnekoh B. Interferon-gamma-dependent in vitro model for the putative keratin 17 autoimmune loop in psoriasis: Exploration of pharmaco- and gene- therapeutic effects. Skin Pharmacol Physiol 2005;18(1):42–54. 13. Shen Z, Wang G, Fan JY, Li W, Liu YF. HLA DR B1*04, *07-restricted epitopes on Keratin 17 for autoreactive T cells in psoriasis. J Dermatol Sci 2005;38(1):25–39. 14. Szeverenyi I, Cassidy AJ, Chung CW, Lee BT, Common JE, Ogg SC, Chen H, Sim SY, Goh WL, Ng KW, Simpson JA, Chee LL, Eng GH, Li B, Lunny DP, Chuon D, Venkatesh A, Khoo KH, McLean WH, Lim YP, Lane EB. The Human Intermediate Filament Database: Compre- hensive information on a gene family involved in many human diseases. Hum Mutat 2008;29(3): 351–360. 15. Omary MB, Coulombe PA, McLean WH. Intermediate ﬁlament proteins and their associated diseases. N Engl J Med 2004;351(20):2087–2100. 16. Porter RM, Lane EB. Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet 2003;19(5):278–285.

Medicinal Research Reviews DOI 10.1002/med 450 r JIN AND WANG

17. Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 2011;508(2):123–137. 18. Windoffer R, Beil M, Magin TM, Leube RE. Cytoskeleton in motion: The dynamics of keratin intermediate filaments in epithelia. J Cell Biol 2011;194(5):669–678. 19. Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, Maltais L, Omary MB, Parry DA, Rogers MA, Wright MW. New consensus nomenclature for mammalian keratins. J Cell Biol 2006;174(2):169–174. 20. Karantza V. Keratins in health and cancer: More than mere epithelial cell markers. Oncogene 2011;30(2):127–138. 21. Gu LH, Coulombe PA. Keratin function in skin epithelia: A broadening palette with surprising shades. Curr Opin Cell Biol 2007;19(1):13–23. 22. McGowan KM, Coulombe PA. Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development. J Cell Biol 1998;143(2):469–486. 23. Troyanovsky SM, Guelstein VI, Tchipysheva TA, Krutovskikh VA, Bannikov GA. Patterns of expression of keratin 17 in human epithelia: Dependency on cell position. J Cell Sci 1989;93(Pt 3):419–426. 24. Kurokawa I, Takahashi K, Moll I, Moll R. Expression of keratins in cutaneous epithelial tu- mors and related disorders—Distribution and clinical significance. Exp Dermatol 2011;20(3): 217–228. 25. De Berker D, Wojnarowska F, Sviland L, Westgate GE, Dawber RP, Leigh IM. Keratin expression in the normal nail unit: Markers of regional differentiation. Br J Dermatol 2000;142(1): 89–96. 26. Bragulla HH, Homberger DG. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J Anat 2009;214(4):516–559. 27. Tong X, Coulombe PA. A novel mouse type I intermediate filament gene, keratin 17n (K17n), exhibits preferred expression in nail tissue. J Invest Dermatol 2004;122(4):965–970. 28. McLean WH, Rugg EL, Lunny DP, Morley SM, Lane EB, Swensson O, Dopping-Hepenstal PJ, Griffiths WA, Eady RA, Higgins C, Et A. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 1995;9(3):273–278. 29. Zang D, Zhou C, He M, Ma X, Zhang J. A novel mutation (p.Arg94Gly) of keratin 17 in a Chinese family with steatocystoma multiplex. Eur J Dermatol 2011;21(1):142–144. 30. McGowan KM, Tong X, Colucci-Guyon E, Langa F, Babinet C, Coulombe PA. Keratin 17 null mice exhibit age- and strain-dependent alopecia. Genes Dev 2002;16(11):1412–1422. 31. Tong X, Coulombe PA. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion. Genes Dev 2006;20(10):1353–1364. 32. Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 2006;441(7091):362–365. 33. Hughes BR, Morris C, Cunliffe WJ, Leigh IM. Keratin expression in pilosebaceous epithelia in truncal skin of acne patients. Br J Dermatol 1996;134(2):247–256. 34. Sugisaki H, YamanakaK, Kakeda M, Kitagawa H, Tanaka K, Watanabe K, Gabazza EC, Kurokawa I, Mizutani H. Increased interferon-gamma, interleukin-12p40 and IL-8 production in Propi- onibacterium acnes-treated peripheral blood mononuclear cells from patient with acne vulgaris: Host response but not bacterial species is the determinant factor of the disease. J Dermatol Sci 2009;55(1):47–52. 35. Depianto D, Kerns ML, Dlugosz AA, Coulombe PA. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet 2010;42(10):910–914. 36. Proby CM, Churchill L, Purkis PE, Glover MT, Sexton CJ, Leigh IM. Keratin 17 expression as a marker for epithelial transformation in viral warts. Am J Pathol 1993;143(6):1667–1678. 37. Mcnairn AJ, Guasch G. Epithelial transition zones: Merging microenvironments, niches, and cellular transformation. Eur J Dermatol 2011;21(Suppl 2):21–28.

Medicinal Research Reviews DOI 10.1002/med KERATIN 17 r 451

38. Pan X, Kane LA, Van Eyk JE, Coulombe PA. Type I keratin 17 protein is phosphorylated on serine 44 by p90 ribosomal protein S6 kinase 1 (RSK1) in a growth- and stress-dependent fashion. J Biol Chem 2011;286(49):42403–42413. 39. Ide M, Kato T, Ogata K, Mochiki E, Kuwano H, Oyama T. Keratin 17 expression correlates with tumor progression and poor prognosis in gastric adenocarcinoma. Ann Surg Oncol 2012;19(11):3506– 3514. 40. Fan J, Shen Z, Wang G, Yang H, Liu Y. Secretory expression of human ScFv against keratin in Pichia pastoris and its effects on cultured keratinocytes. Arch Dermatol Res 2009;301(5):367–372. 41. Shen Z, Chen L, Liu YF, Gao TW, Wang G, Fan XL, Fan JY, Fan PS, Li CY, Liu B, Dang YP, Li CX. Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis. J Am Acad Dermatol 2006;54(6):992–1002. 42. de Jong EM, van Vlijmen IM, van Erp PE, Ramaekers FC, Troyanovski SM, van de Kerkhof PC. Keratin 17: A useful marker in anti-psoriatic therapies. Arch Dermatol Res 1991;283(7):480–482. 43. Leigh IM, Navsaria H, Purkis PE, McKay IA, Bowden PE, Riddle PN. Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro. Br J Dermatol 1995;133(4):501–511. 44. Thewes M, Stadler R, Korge B, Mischke D. Normal psoriatic epidermis expression of hyperproliferation-associated keratins. Arch Dermatol Res 1991;283(7):465–471. 45. Bonnekoh B, Huerkamp C, Wevers A, Geisel J, Sebok B, Bange FC, Greenhalgh DA, Bottger EC, Krieg T, Mahrle G. Up-regulation of keratin 17 expression in human HaCaT keratinocytes by interferon-gamma. J Invest Dermatol 1995;104(1):58–61. 46. Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y, Wang G. IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. J Invest Dermatol 2011;131(12):2401–2408. 47. Zhang W, Dang E, Shi X, Jin L, Feng Z, Hu L, Wu Y, Wang G. The pro-inﬂammatory cytokine IL-22 up-regulates keratin 17 Expression in keratinocytes via STAT3 and ERK1/2. PLoS One 2012;7(7):e40797. 48. Bowcock AM, Krueger JG. Getting under the skin: The immunogenetics of psoriasis. Nat Rev Immunol 2005;5(9):699–711. 49. Mitra A, Fallen RS, Lima HC. Cytokine-based therapy in psoriasis. Clin Rev Allergy Immunol 2013;44(2):173–182. 50. Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366(13):1190–1199. 51. Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EH, Baumgartner S. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012;366(13):1181–1189. 52. Johnson-Huang LM, Suarez-Farinas M, Pierson KC, Fuentes-Duculan J, Cueto I, Lentini T, Sullivan-Whalen M, Gilleaudeau P, Krueger JG, Haider AS, Lowes MA. A single intradermal injection of IFN-gamma induces an inﬂammatory state in both non-lesional psoriatic and healthy skin. J Invest Dermatol 2012;132(4):1177–1187. 53. Flohr T, Buwitt U, Bonnekoh B, Decker T, Bottger EC. Interferon-gamma regulates expression of a novel keratin class I gene. Eur J Immunol 1992;22(4):975–979. 54. Troyanovsky SM, Leube RE, Franke WW. Characterization of the human gene encoding cytokeratin 17 and its expression pattern. Eur J Cell Biol 1992;59(1):127–137. 55. Jiang CK, Flanagan S, Ohtsuki M, Shuai K, Freedberg IM, Blumenberg M. Disease-activated transcription factor: Allergic reactions in human skin cause nuclear translocation of STAT-91 and induce synthesis of keratin K17. Mol Cell Biol 1994;14(7):4759–4769. 56. Vogel U, Denecke B, Troyanovsky SM, Leube RE, Bottger EC. Transcriptional activation of psoriasis-associated cytokeratin K17 by interferon-gamma. Analysis of gamma-interferon activation sites. Eur J Biochem 1995;227(1–2):143–149.

Medicinal Research Reviews DOI 10.1002/med 452 r JIN AND WANG

57. Komine M, Freedberg IM, Blumenberg M. Regulation of epidermal expression of keratin K17 in inflammatory skin diseases. J Invest Dermatol 1996;107(4):569–575. 58. Wei L, Debets R, Hegmans JJ, Benner R, Prens EP. IL-1 beta and IFN-gamma induce the regen- erative epidermal phenotype of psoriasis in the transwell skin organ culture system. IFN-gamma up-regulates the expression of keratin 17 and keratinocyte transglutaminase via endogenous IL-1 production. J Pathol 1999;187(3):358–364. 59. Gudmundsdottir AS, Sigmundsdottir H, Sigurgeirsson B, Good MF, Valdimarsson H, Jonsdottir I. Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis? Clin Exp Immunol 1999;117(3):580–586. 60. Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H. Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells. Clin Exp Immunol 2004;138(1):83–93. 61. Tervaert WC, Esseveld H. A study of the incidence of haemolytic streptococci in the throat in patients with psoriasis vulgaris, with reference to their role in the pathogenesis of this disease. Dermatologica 1970;140(5):282–290. 62. Leung DY, Travers JB, Giorno R, Norris DA, Skinner R, Aelion J, Kazemi LV, Kim MH, Trumble AE, Kotb M, Et A. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 1995;96(5):2106–2112. 63. Davison SC, Allen MH, Mallon E, Barker JN. Contrasting patterns of streptococcal superantigen- induced T-cell proliferation in guttate vs. chronic plaque psoriasis. Br J Dermatol 2001;145(2):245– 251. 64. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370(9583):263– 271. 65. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, Kristinsson KG, Valdimarsson H. Strepto- coccal throat infections and exacerbation of chronic plaque psoriasis: A prospective study. Br J Dermatol 2003;149(3):530–534. 66. Smeesters PR, McMillan DJ, Sriprakash KS. The streptococcal M protein: A highly versatile molecule. Trends Microbiol 2010;18(6):275–282. 67. Valdimarsson H, Thorleifsdottir RH, Sigurdardottir SL, Gudjonsson JE, Johnston A. Psoriasis—as an autoimmune disease caused by molecular mimicry. Trends Immunol 2009;30(10):494–501. 68. Nozawa H, Kishibe K, Takahara M, Harabuchi Y. Expression of cutaneous lymphocyte-associated antigen (CLA) in tonsillar T-cells and its induction by in vitro stimulation with alpha-streptococci in patients with pustulosis palmaris et plantaris (PPP). Clin Immunol 2005;116(1):42–53. 69. Wang G, Liu YF, Li CY, Lu N, Gao TW, Hua B, Wang Y. Cloning and characterization of antikeratin human antibodies using a semisynthetic phage antibody library. Arch Dermatol Res 2004;296(6):270–277. 70. Fan L, Busser BW, Lifsted TQ, Oukka M, Lo D, Laufer TM. Antigen presentation by keratinocytes directs autoimmune skin disease. Proc Natl Acad Sci U S A 2003;100(6):3386–3391. 71. Steinman RM. Decisions about dendritic cells: Past, present, and future. Annu Rev Immunol 2012;30:1–22. 72. Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med 1999;341(24):1817–1828. 73. Morizane S, Yamasaki K, Muhleisen B, Kotol PF, Murakami M, Aoyama Y, Iwatsuki K, Hata T, Gallo RL. Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J Invest Dermatol 2012;132(1):135–143. 74. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schroder JM, Liu YJ, Gilliet M. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449(7162):564–569. 75. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, Homey B, Barrat FJ, Zal T, Gilliet M. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 2009;206(9):1983–1994.

Medicinal Research Reviews DOI 10.1002/med KERATIN 17 r 453

76. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, Gonzalez J, Krueger JG, Lowes MA. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009;129(1):79–88. 77. Eyerich S, Onken AT, Weidinger S, Franke A, Nasorri F, Pennino D, Grosber M, Pfab F, Schmidt- Weber CB, Mempel M, Hein R, Ring J, Cavani A, Eyerich K. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med 2011;365(3):231–238. 78. Quaglino P, Bergallo M, Ponti R, Barberio E, Cicchelli S, Buffa E, Comessatti A, Costa C, Terlizzi ME, Astegiano S, Novelli M, Cavallo R, Bernengo MG. Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: Modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical response. Dermatology 2011;223(1):57–67. 79. Raychaudhuri SP. Role of IL-17 in psoriasis and psoriatic arthritis. Clin Rev Allergy Immunol 2013;44(2):183–193. 80. Balato A, Unutmaz D, Gaspari AA. Natural killer T cells: An unconventional T-cell subset with diverse effector and regulatory functions. J Invest Dermatol 2009;129(7):1628–1642. 81. Gunther C, Carballido-Perrig N, Kaesler S, Carballido JM, Biedermann T. CXCL16 and CXCR6 are upregulated in psoriasis and mediate cutaneous recruitment of human CD8+ T cells. J Invest Dermatol 2012;132(3 Pt 1):626–634. 82. Res PC, Piskin G, de Boer OJ, van der Loos CM, Teeling P, Bos JD, Teunissen MB. Overrepresen- tation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PLoS One 2010;5(11):e14108. 83. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010;130(5):1373–1383. 84. Krueger JG, Fretzin S, Suarez-Farinas M, Haslett PA, Phipps KM, Cameron GS, McColm J, Katcherian A, Cueto I, White T, Banerjee S, Hoffman RW. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol 2012;130(1):145– 154. 85. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W. Interleukin- 22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007;445(7128):648–651. 86. Ouyang W. Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev 2010;21(6):435–441. 87. Kryczek I, Wei S, Gong W, Shu X, Szeliga W, Vatan L, Chen L, Wang G, Zou W. Cutting edge: IFN-gamma enables APC to promote memory Th17 and abate Th1 cell development. J Immunol 2008;181(9):5842–5846. 88. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanza- vecchia A, Sallusto F. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 2012;484(7395):514–518. 89. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 2009;129(6):1339–1350. 90. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb A, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009;60(4): 643–659. 91. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009;61(3):451– 485. 92. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb A, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care

Medicinal Research Reviews DOI 10.1002/med 454 r JIN AND WANG

for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy.J Am Acad Dermatol 2010;62(1): 114–135. 93. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, Lebwohl M, Koo JY, Elmets CA, Korman NJ, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008;58(5):826–850. 94. Radoja N, Komine M, Jho SH, Blumenberg M, Tomic-Canic M. Novel mechanism of steroid action in skin through glucocorticoid receptor monomers. Mol Cell Biol 2000;20(12):4328–4339. 95. Ramot Y, Paus R, Tiede S, Zlotogorski A. Endocrine controls of keratin expression. Bioessays 2009;31(4):389–399. 96. Radoja N, Diaz DV, Minars TJ, Freedberg IM, Blumenberg M, Tomic-Canic M. Speciﬁc organi- zation of the negative response elements for retinoic acid and thyroid hormone receptors in keratin gene family. J Invest Dermatol 1997;109(4):566–572. 97. Bonnekoh B, Bockelmann R, Ambach A, Gollnick H. Dithranol and dimethylfumarate suppress the interferon-gamma-induced up-regulation of cytokeratin 17 as a putative psoriasis autoantigen in vitro. Skin Pharmacol Appl Skin Physiol 2001;14(4):217–225. 98. Tu HQ, Li XY, Tang MY, Gao JW, Xu LF, Chen ZQ, Gu H. Effects of tacrolimus on IFN-gamma signaling in keratinocytes: Possible mechanisms by which tacrolimus affects IFN-gamma-dependent skin inﬂammation. Eur J Dermatol 2011;21(1):22–31. 99. Takei-Taniguchi R, Imai Y, Ishikawa C, Sakaguchi Y, Nakagawa N, Tsuda T, Hollenberg MD, Yamanishi K. Interleukin-17- and protease-activated receptor 2-mediated production of CXCL1 and CXCL8 modulated by cyclosporine A, vitamin D3 and glucocorticoids in human keratinocytes. J Dermatol 2012;39(7):625–631. 100. Chang T, Sun L, Wang Y, Wang D, Li W, Li C, Gao T, Liu Y, Wang G. Inhibition of keratin 17 expression with antisense and RNAi strategies: Exploring novel therapy for psoriasis. Exp Dermatol 2011;20(7):555–560. 101. Milisavljevic V, Freedberg IM, Blumenberg M. Characterization of nuclear protein binding sites in the promoter of keratin K17 gene. Dna Cell Biol 1996;15(1):65–74.

Liang Jin received his M.Sc. in Biochemistry and Molecular Biology from the Fourth Military Medical University in Xi’an, China. He is currently a Ph.D. student at the Department of Der- matology at the Xijing Hospital of the Fourth Military Medical University. His major research interests include the immunological pathogenesis of psoriasis and the biological characteristics and manipulation of keratin 17.

Gang Wang received his M.D. and Ph.D. in Dermatology from the Fourth Military Medical University. He is the Chairman and a Professor at the Department of Dermatology at the Xijing Hospital of the Fourth Military Medical University. His major research interests include psoriasis and bullous diseases, especially the immunological pathogenesis of psoriasis and bullous pemphigoid.

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