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348 Topical RORγ inverse agonist alleviate preclinical models of psoriasis
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High biofilm-producing Staphylococcus aureus associates with severe atopic dermatitis and its proliferation is increased by inflammatory cytokines E Di Domenico1, I Cavallo1, L Toma2, B Capitanio3 and F Ensoli1 1 Clinical Pathology and Microbiology, San Gallicano, Rome, Italy, 2 Infectious Disease Consultant, Regina Elena National Cancer Institute, Rome, Italy and 3 Department of Dermatology, San Gallicano, Rome, Italy Atopic dermatitis (AD) is an inflammatory disease characterized by impaired epidermal barrier function, cutaneous inflammation and more susceptible to Staphylococcus aureus colonization. In this stydy we investigate the impact of biofilm-producing S. aureus on AD severity. Additionally, we assessed whether the inflammatory cytokine mileau present in AD might provide a selective advantage to biofilm-producing S. aureus. The severity of AD was measured from 81 pediatric patients by the scoring atopic dermatitis index (SCORAD) and the clinical expression of disease was classified as low, medium or high. Biofilm production by S. aureus isolates was measured by the clinical BioFilm Ring Test. In vitro studies were performed to evaluate the response of S. aureus strains to different concentrations of interleukin (IL)-b, interferon g (IFN- g), and interleukin (IL)-6. Of the patients analyzed, 25 were classified as low, 30 moderate and 26 as high SCORAD. The presence of S. aureus correlated with the severity of the skin lesion. Only 28% of the patients with low SCORAD were colonized whereas, the percentage increased to 56.6% in patients with moderate SCORAD and raised to 76.9% in patients with high SCORAD. S. aureus biofilm production was significantly higher (P<0.01) in patients with a more severe form of the disease as compared to those individuals with a low SCORAD. Furthermore, the growth of both biofilm and planktonic S. aureus isolates was enhanced in the presence of IL1-b and IFN- g but not with IL-6 in a concentration-dependent manner. Biofilm production by AD-associated S. aureus may play major roles in promoting chronicity and disease severity. In addition, the growth enhancement of S. aureus isolates induced by IL1-b and IFN-g, provides evidence for a novel pathogenetic circuitry responsible for bacterial persistence and disease exacerbation.
Regulated expression of CD73 by subsets of dendritic cells in skin is crucial for modulating contact hypersensitivity reactions in mice C Silva-Vilches, A Neuberger, S Ring, A Enk and K Mahnke Dpt. of Dermatology, University Hospital Heidelberg, Heidelberg, Germany The ecto-5’-nucleotidase CD73 converts extracellular adenosine monophosphate, which is a product of ATP degradation by CD39, to adenosine (ADO). Because ADO has well established anti-inflammatory effects, expression of CD73 by different types of skin cells may be crucial for the outcome of contact hypersensitivity (CHS) reactions. At first we analysed expression of CD39 and CD73, respectively, by different subsets of skin dendritic cells (DCs) and found ubiquitous expression of CD39 on all defined DC subsets. In contrast, CD73 was expressed by only 3%-8% of CD207+ Langerhans cells (LC) and other dermal DCs, respectively. Similar expression patterns were observed in skin migrating (sm) DCs in the lymph node under steady state conditions. However, application of the hapten TNCB induced surface-expression of CD73 in all cells, resulting in 20%-30% CD73+ DC and LC, respectively. This increased expression of CD73 was persistent, as it was also detectable in smDC 24h-48h after sensitization. Next, CD73 deficient (CD73KO) mice were subjected to a classical TNCB-induced CHS protocol and we found increased ear swelling reactions as compared to wild type mice, indicating rather down-modulatory functions of CD73 in CHS reactions. To accurately assess the tolerogenic functions of CD73 expression by smDC in CHS reactions, we established a tolerance model whereby application of DNTB renders animals tolerant to subsequent sensitization with DNFB. Here we show that both, the tolerogen DNTB as well as the sensitizer DNFB induced migration of similar DC subsets from skin to lymph nodes. But after DNTB application substantially higher expression levels of CD73 was observed in particular in CD11b+ as well as in CD207+CD103+ smDC. Of note, CD73KO animals were resistant to tolerization by DNTB. Thus, these data indicate a substantial role of CD73+ skin DC in regulating tolerance to haptens.
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Topical RORg inverse agonist alleviate preclinical models of psoriasis C Hervouet, F Bihl, G Ouvry, C Bouix-Peter, C Chaussade, D Piwnica, V Julia, L Hennequin, E Vial and F Hacini-Rachinel Research, Nestle´ Skin Health, Sophia-Antipolis, France Psoriasis is a common chronic inflammatory disease involving dynamic interactions between the immune system and the skin. Histologically, psoriatic lesions are characterized by epidermal hyperplasia, immune cell infiltration in the dermis and hypervascularization. Recently developped IL-17-targeting monoclonal antibodies have proven to be successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Within psoriatic lesions, IL-17 can be produced by several cell types, including Th17 cells, gd T cells, CD8 T cells, innate lymphoid cells (ILC3s), neutrophils and possibly mast cells. Although several transcription factors may be important, the development and maintenance of IL-17 producing cells is controlled by the nuclear receptor retinoid related orphan receptor gamma t (RORgt). RORgt is both necessary and sufficient for IL-17 expression and Th17 lineage differentiation in both humans and mice. In addition, imiquimod-induced psoriasiform-skin inflammation in mice is attenuated by RORgt gene deficiency as well as by oral treatment with RORg inihibitors. Here we describe compound A, a potent and selective inverse agonist of the human RORg receptor specifically designed for the topical route. Compound A potently inhibits IL-17A release from human and murine CD4+ T cells with no impact on regulatory T cell polarization. In the imiquimod-induced psoriasiform skin inflammation, topical compound A dose-dependently downregulates the expression of skin IL-17 mRNA; decreases the frequency of skin IL17-producing gd T cells as well as the epidermis thickness. Finally, similarly to topical corticosteroid, systemic anti-IL-17 mAb, and oral RORg inhibitor, topical treatment with compound A decreases the hallmarks of psoriasis in a humanized mouse model. Altogether these results suggest that compound A, our topical small molecule inhibitor targeting RORg, may represent an alternative topical medicine for psoriasis patients ineligible for systemic treatments.
Induction of IL-10-balanced immune profiles following exposure to LTA from Staphylococcus epidermidis T Volz1, S Kaesler1, C Draing3, T Hartung3,4, M Ro¨cken2, Y Skabytska1 and T Biedermann1 1 Department of Dermatology and Allergology, Technical University Munich, Munich, Germany, 2 Department of Dermatology, Eberhard Karls University, Tu¨bingen, Germany, 3 Center for Alternatives to Animal Testing Europe, University of Konstanz, Konstanz, Germany and 4 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD Staphylococcus epidermidis colonizes human skin without signs of inflammation, but a dominance of S. epidermidis and S. aureus is characteristic for cutaneous microbial dysbiosis in atopic dermatitis (AD). While S. aureus is considered to trigger AD, the role of S. epidermidis is less well determined. We characterized consequences of innate immune sensing of lipoteichoic acid (LTA) derived from S. epidermidis (epi-LTA) or S. aureus (aureus-LTA). Exposure to epi-LTA or aureus-LTA activated murine DC via the TLR2-MyD88 pathway, however, resulting in divergent immune profiles. Differences between LTAs were significant for IL-6, IL-12p40, and IL-12p70 but not for IL-10 best reflected by the IL-12p70-to-IL-10 ratio being IL-10-balanced (near 1) for epi-LTA but pro-inflammatory (>4) for aureus-LTA. DC exposed to the LTAs again unequivocally activated OVA-specific CD4+ T cells, however, while T-cell derived IL-10 was equivalent between LTAs, IFN-g and IL-17 were significantly reduced for epi-LTA. Mimicking acute AD by exposing DC to IL-4 and LTAs revealed that IL-4 significantly and uniformly suppressed epi-LTA induced cytokine production keeping the IL12p70-to-IL-10 ratio balanced. In contrast, exposure of DC to aureus-LTA and IL-4 enhanced IL-12p70 but suppressed IL-10 levels further unbalancing the IL-12p70-to-IL-10 ratio. These data demonstrate opposing immune consequences following exposure to staphylococcal LTAs. Epi-LTA induced IL-10-balanced, aureus-LTA pro-inflammatory immune profiles.
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Efficacy of topical endocannabinoid membrane transporter inhibitor WOL067-531 in a double blinded, placebo controlled crossover study in a colony of atopic beagles K Ahrens2, R Sanford2, M Soeberdt1, U Knie1, C Abels1 and R Marsella2 1 Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany and 2 Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL The endocannabinoid system (ECS) of the skin is implicated in multiple regulatory functions both in health and disease in the skin and plays an important role in inflammatory processes in the skin. In this study we tested a topical endocannabinoid membrane transporter (EMT) inhibitor (WOL067-531) in a gel formulation compared to placebo (vehicle) for atopic dermatitis (AD) using atopic beagles sensitized to house dust mites (HDM). Nineteen dogs were randomly assigned to two groups: one received active ingredient (2 mg/cm2) on the inguinal area and the other vehicle for 21 d. Dogs were challenged epicutaneously with HDM twice weekly for 28 d. Product application started after the third challenge (d 8), twice daily except for day of challenges (once daily, 6 h after challenge). Canine Atopic Dermatitis and Extent Severity Index (CADESI-03) was assessed before and 6 h after first challenge of the week. Pruritus was assessed on the same days as CADESI. After a 4-week washout, dogs were crossed-over and the study repeated. In the vehicle group, on d 15 and 22, CADESI-03 scores in inguinal area were significantly higher after challenge (mean difference of 16.34 p¼0.009 and 7.42 p¼0.048, respectively), whereas in treatment group no significant increase was detected on both days (mean difference of 2.42 p¼ 0.32 and 2.58 p¼0.32, respectively). Moreover, the effect of time on pruritus global scores (p¼0.053) approached significance for treatment group. Significant decrease on pruritic acts both on inguinal area and overall (p¼0.048 and p¼0.032, respectively) was found in the treatment group. In conclusion, this topical EMT-inhibitor reduced flares after allergen exposure regarding severity of skin lesions and intensity of pruritus in a canine model of AD. Further studies will show the usefulness of topical EMT-inhibitors in the treatment of inflammatory and pruritic skin diseases in patients.
S252 Journal of Investigative Dermatology (2017), Volume 137
Keratin 17 is ubiquitinated by Trim21 in human keratinocytes in psoriasis L Yang, L Jin, X Bai and G Wang dermatology, Xijing Hospital, the Fourth Military Medical School, Xi’an, China Keratin 17 (K17) is a type I intermediate filament which is highly expressed in psoriatic epidermis. Studies on K17 uncover several role for K17, including mechanical support, regulation of cell proliferation. We previously proposed a K17/T-cell/cytokine autoimmune loop in which K17 could be induced by inflammatory cytokine. Yet, little is known about the regulation of K17 expression via post-translational modification. Ubiquitination is one of the most important post-translational modifications that modulate the functions of proteins. UbiNet software predicated several ubiquitination sites on human K17. We sought to determine whether K17 underwent ubiquitination by dysregulated E3 ligase in psoriasis, which regulated the protein levels of K17 and contributed to the pathogenesis of psoriasis. To assess whether K17 is ubiquitinated in human keratinocytes, we employed immunoprecipitation. We initially found that K17 is ubiquitinated in normal human keratinocytes HaCaT cells, while with a higher level of ubiquitination observed in psoriatic keratinocytes induced by “psoriasis-like” cytokines. Moreover, immunoprecipitation coupled with mass spectrometry identified the candidate E3 ligase for K17, Trim21. We further confirmed the direct interaction between Trim21 and K17 by immunoprecipitation and immunofluorescence in HaCaT cells. Importantly, Trim21 mRNA and protein levels were significantly elevated in psoriatic epidermis comparing with normal epidermis, as assessed by RT-PCR, western blotting, immunofluorescence and immunohistochemistry. Overexpression of Trim21 led to activation of K17, but not degradation, which can be partly illustrated by our finding that K17 is ubiquitinated by Trim21 via K63-linkage. Taken together, our data suggest a previously unrecognized role for ubiquitination in regulating protein level of K17 in psoriasis, further indicating a novel mechanism in the pathogenesis of psoriasis. Trim21, which regulated K17 activation by ubiquitination, provides a potential target for interrupting K17 activation in the treatment of psoriasis.
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High biofilm-producing Staphylococcus aureus associates with severe atopic dermatitis and its proliferation is increased by inflammatory cytokines E Di Domenico1, I Cavallo1, L Toma2, B Capitanio3 and F Ensoli1 1 Clinical Pathology and Microbiology, San Gallicano, Rome, Italy, 2 Infectious Disease Consultant, Regina Elena National Cancer Institute, Rome, Italy and 3 Department of Dermatology, San Gallicano, Rome, Italy Atopic dermatitis (AD) is an inflammatory disease characterized by impaired epidermal barrier function, cutaneous inflammation and more susceptible to Staphylococcus aureus colonization. In this stydy we investigate the impact of biofilm-producing S. aureus on AD severity. Additionally, we assessed whether the inflammatory cytokine mileau present in AD might provide a selective advantage to biofilm-producing S. aureus. The severity of AD was measured from 81 pediatric patients by the scoring atopic dermatitis index (SCORAD) and the clinical expression of disease was classified as low, medium or high. Biofilm production by S. aureus isolates was measured by the clinical BioFilm Ring Test. In vitro studies were performed to evaluate the response of S. aureus strains to different concentrations of interleukin (IL)-b, interferon g (IFN- g), and interleukin (IL)-6. Of the patients analyzed, 25 were classified as low, 30 moderate and 26 as high SCORAD. The presence of S. aureus correlated with the severity of the skin lesion. Only 28% of the patients with low SCORAD were colonized whereas, the percentage increased to 56.6% in patients with moderate SCORAD and raised to 76.9% in patients with high SCORAD. S. aureus biofilm production was significantly higher (P<0.01) in patients with a more severe form of the disease as compared to those individuals with a low SCORAD. Furthermore, the growth of both biofilm and planktonic S. aureus isolates was enhanced in the presence of IL1-b and IFN- g but not with IL-6 in a concentration-dependent manner. Biofilm production by AD-associated S. aureus may play major roles in promoting chronicity and disease severity. In addition, the growth enhancement of S. aureus isolates induced by IL1-b and IFN-g, provides evidence for a novel pathogenetic circuitry responsible for bacterial persistence and disease exacerbation.
Regulated expression of CD73 by subsets of dendritic cells in skin is crucial for modulating contact hypersensitivity reactions in mice C Silva-Vilches, A Neuberger, S Ring, A Enk and K Mahnke Dpt. of Dermatology, University Hospital Heidelberg, Heidelberg, Germany The ecto-5’-nucleotidase CD73 converts extracellular adenosine monophosphate, which is a product of ATP degradation by CD39, to adenosine (ADO). Because ADO has well established anti-inflammatory effects, expression of CD73 by different types of skin cells may be crucial for the outcome of contact hypersensitivity (CHS) reactions. At first we analysed expression of CD39 and CD73, respectively, by different subsets of skin dendritic cells (DCs) and found ubiquitous expression of CD39 on all defined DC subsets. In contrast, CD73 was expressed by only 3%-8% of CD207+ Langerhans cells (LC) and other dermal DCs, respectively. Similar expression patterns were observed in skin migrating (sm) DCs in the lymph node under steady state conditions. However, application of the hapten TNCB induced surface-expression of CD73 in all cells, resulting in 20%-30% CD73+ DC and LC, respectively. This increased expression of CD73 was persistent, as it was also detectable in smDC 24h-48h after sensitization. Next, CD73 deficient (CD73KO) mice were subjected to a classical TNCB-induced CHS protocol and we found increased ear swelling reactions as compared to wild type mice, indicating rather down-modulatory functions of CD73 in CHS reactions. To accurately assess the tolerogenic functions of CD73 expression by smDC in CHS reactions, we established a tolerance model whereby application of DNTB renders animals tolerant to subsequent sensitization with DNFB. Here we show that both, the tolerogen DNTB as well as the sensitizer DNFB induced migration of similar DC subsets from skin to lymph nodes. But after DNTB application substantially higher expression levels of CD73 was observed in particular in CD11b+ as well as in CD207+CD103+ smDC. Of note, CD73KO animals were resistant to tolerization by DNTB. Thus, these data indicate a substantial role of CD73+ skin DC in regulating tolerance to haptens.
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Topical RORg inverse agonist alleviate preclinical models of psoriasis C Hervouet, F Bihl, G Ouvry, C Bouix-Peter, C Chaussade, D Piwnica, V Julia, L Hennequin, E Vial and F Hacini-Rachinel Research, Nestle´ Skin Health, Sophia-Antipolis, France Psoriasis is a common chronic inflammatory disease involving dynamic interactions between the immune system and the skin. Histologically, psoriatic lesions are characterized by epidermal hyperplasia, immune cell infiltration in the dermis and hypervascularization. Recently developped IL-17-targeting monoclonal antibodies have proven to be successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Within psoriatic lesions, IL-17 can be produced by several cell types, including Th17 cells, gd T cells, CD8 T cells, innate lymphoid cells (ILC3s), neutrophils and possibly mast cells. Although several transcription factors may be important, the development and maintenance of IL-17 producing cells is controlled by the nuclear receptor retinoid related orphan receptor gamma t (RORgt). RORgt is both necessary and sufficient for IL-17 expression and Th17 lineage differentiation in both humans and mice. In addition, imiquimod-induced psoriasiform-skin inflammation in mice is attenuated by RORgt gene deficiency as well as by oral treatment with RORg inihibitors. Here we describe compound A, a potent and selective inverse agonist of the human RORg receptor specifically designed for the topical route. Compound A potently inhibits IL-17A release from human and murine CD4+ T cells with no impact on regulatory T cell polarization. In the imiquimod-induced psoriasiform skin inflammation, topical compound A dose-dependently downregulates the expression of skin IL-17 mRNA; decreases the frequency of skin IL17-producing gd T cells as well as the epidermis thickness. Finally, similarly to topical corticosteroid, systemic anti-IL-17 mAb, and oral RORg inhibitor, topical treatment with compound A decreases the hallmarks of psoriasis in a humanized mouse model. Altogether these results suggest that compound A, our topical small molecule inhibitor targeting RORg, may represent an alternative topical medicine for psoriasis patients ineligible for systemic treatments.
Induction of IL-10-balanced immune profiles following exposure to LTA from Staphylococcus epidermidis T Volz1, S Kaesler1, C Draing3, T Hartung3,4, M Ro¨cken2, Y Skabytska1 and T Biedermann1 1 Department of Dermatology and Allergology, Technical University Munich, Munich, Germany, 2 Department of Dermatology, Eberhard Karls University, Tu¨bingen, Germany, 3 Center for Alternatives to Animal Testing Europe, University of Konstanz, Konstanz, Germany and 4 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD Staphylococcus epidermidis colonizes human skin without signs of inflammation, but a dominance of S. epidermidis and S. aureus is characteristic for cutaneous microbial dysbiosis in atopic dermatitis (AD). While S. aureus is considered to trigger AD, the role of S. epidermidis is less well determined. We characterized consequences of innate immune sensing of lipoteichoic acid (LTA) derived from S. epidermidis (epi-LTA) or S. aureus (aureus-LTA). Exposure to epi-LTA or aureus-LTA activated murine DC via the TLR2-MyD88 pathway, however, resulting in divergent immune profiles. Differences between LTAs were significant for IL-6, IL-12p40, and IL-12p70 but not for IL-10 best reflected by the IL-12p70-to-IL-10 ratio being IL-10-balanced (near 1) for epi-LTA but pro-inflammatory (>4) for aureus-LTA. DC exposed to the LTAs again unequivocally activated OVA-specific CD4+ T cells, however, while T-cell derived IL-10 was equivalent between LTAs, IFN-g and IL-17 were significantly reduced for epi-LTA. Mimicking acute AD by exposing DC to IL-4 and LTAs revealed that IL-4 significantly and uniformly suppressed epi-LTA induced cytokine production keeping the IL12p70-to-IL-10 ratio balanced. In contrast, exposure of DC to aureus-LTA and IL-4 enhanced IL-12p70 but suppressed IL-10 levels further unbalancing the IL-12p70-to-IL-10 ratio. These data demonstrate opposing immune consequences following exposure to staphylococcal LTAs. Epi-LTA induced IL-10-balanced, aureus-LTA pro-inflammatory immune profiles.
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Efficacy of topical endocannabinoid membrane transporter inhibitor WOL067-531 in a double blinded, placebo controlled crossover study in a colony of atopic beagles K Ahrens2, R Sanford2, M Soeberdt1, U Knie1, C Abels1 and R Marsella2 1 Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany and 2 Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL The endocannabinoid system (ECS) of the skin is implicated in multiple regulatory functions both in health and disease in the skin and plays an important role in inflammatory processes in the skin. In this study we tested a topical endocannabinoid membrane transporter (EMT) inhibitor (WOL067-531) in a gel formulation compared to placebo (vehicle) for atopic dermatitis (AD) using atopic beagles sensitized to house dust mites (HDM). Nineteen dogs were randomly assigned to two groups: one received active ingredient (2 mg/cm2) on the inguinal area and the other vehicle for 21 d. Dogs were challenged epicutaneously with HDM twice weekly for 28 d. Product application started after the third challenge (d 8), twice daily except for day of challenges (once daily, 6 h after challenge). Canine Atopic Dermatitis and Extent Severity Index (CADESI-03) was assessed before and 6 h after first challenge of the week. Pruritus was assessed on the same days as CADESI. After a 4-week washout, dogs were crossed-over and the study repeated. In the vehicle group, on d 15 and 22, CADESI-03 scores in inguinal area were significantly higher after challenge (mean difference of 16.34 p¼0.009 and 7.42 p¼0.048, respectively), whereas in treatment group no significant increase was detected on both days (mean difference of 2.42 p¼ 0.32 and 2.58 p¼0.32, respectively). Moreover, the effect of time on pruritus global scores (p¼0.053) approached significance for treatment group. Significant decrease on pruritic acts both on inguinal area and overall (p¼0.048 and p¼0.032, respectively) was found in the treatment group. In conclusion, this topical EMT-inhibitor reduced flares after allergen exposure regarding severity of skin lesions and intensity of pruritus in a canine model of AD. Further studies will show the usefulness of topical EMT-inhibitors in the treatment of inflammatory and pruritic skin diseases in patients.
S252 Journal of Investigative Dermatology (2017), Volume 137
Keratin 17 is ubiquitinated by Trim21 in human keratinocytes in psoriasis L Yang, L Jin, X Bai and G Wang dermatology, Xijing Hospital, the Fourth Military Medical School, Xi’an, China Keratin 17 (K17) is a type I intermediate filament which is highly expressed in psoriatic epidermis. Studies on K17 uncover several role for K17, including mechanical support, regulation of cell proliferation. We previously proposed a K17/T-cell/cytokine autoimmune loop in which K17 could be induced by inflammatory cytokine. Yet, little is known about the regulation of K17 expression via post-translational modification. Ubiquitination is one of the most important post-translational modifications that modulate the functions of proteins. UbiNet software predicated several ubiquitination sites on human K17. We sought to determine whether K17 underwent ubiquitination by dysregulated E3 ligase in psoriasis, which regulated the protein levels of K17 and contributed to the pathogenesis of psoriasis. To assess whether K17 is ubiquitinated in human keratinocytes, we employed immunoprecipitation. We initially found that K17 is ubiquitinated in normal human keratinocytes HaCaT cells, while with a higher level of ubiquitination observed in psoriatic keratinocytes induced by “psoriasis-like” cytokines. Moreover, immunoprecipitation coupled with mass spectrometry identified the candidate E3 ligase for K17, Trim21. We further confirmed the direct interaction between Trim21 and K17 by immunoprecipitation and immunofluorescence in HaCaT cells. Importantly, Trim21 mRNA and protein levels were significantly elevated in psoriatic epidermis comparing with normal epidermis, as assessed by RT-PCR, western blotting, immunofluorescence and immunohistochemistry. Overexpression of Trim21 led to activation of K17, but not degradation, which can be partly illustrated by our finding that K17 is ubiquitinated by Trim21 via K63-linkage. Taken together, our data suggest a previously unrecognized role for ubiquitination in regulating protein level of K17 in psoriasis, further indicating a novel mechanism in the pathogenesis of psoriasis. Trim21, which regulated K17 activation by ubiquitination, provides a potential target for interrupting K17 activation in the treatment of psoriasis.