Interaction of Wnt5a with Notch1 is Critical for the Pathogenesis of Psoriasis

Background Psoriasis is characterized by uncontrolled hyperproliferation, aberrant differentiation, and dermal infiltration of immune cells. Recent studies have reported that Wnt5a and Notch1 signaling are altered in psoriatic skin lesions. Objective We aimed to investigate the interaction of Wnt5a with Notch 1 with respect to inflammation-mediated epidermal hyperproliferation in psoriasis. Methods Expression of Wnt5a and Notch1 signaling-related proteins were examined in psoriatic skin biopsies. Wnt5a was upregulated in human keratinocytes by treating the cells with its recombinant form (rWnt5a). Results In psoriatic lesions, expression of Wnt5a increased while that of Notch1 decreased when compared to that in non-lesional and normal skin. Treatment with rWnt5a increased the proliferation of keratinocytes and increased their secretion of interleukin (IL)-23, IL-12, and tumor necrosis factor (TNF)-α. Further, exposure of keratinocytes to IL-1α, TNF-α, transforming growth factor-α, and interferon-γ downregulated Notch1 as well as HES 1, which is downstream to Notch1, but increased the Wnt5a levels. The upregulated Wnt5a in keratinocytes downregulated both Notch1 and HES1. Conclusion Our data suggest that Wnt5a and Notch1 signaling exert counteracting influences on each other and are involved, in part, in the pathomechanism of psoriasis.

[1]  Yingwei Chen,et al.  Overexpression of Wnt5a in mouse epidermis causes no psoriasis phenotype but an impairment of hair follicle anagen development , 2014, Experimental dermatology.

[2]  S. Takekoshi,et al.  Notch Signaling May Be Involved in the Abnormal Differentiation of Epidermal Keratinocytes in Psoriasis , 2014, Acta histochemica et cytochemica.

[3]  Jung-Eun Kim,et al.  Notch Intracellular Domain Expression in Various Skin Fibroproliferative Diseases , 2014, Annals of dermatology.

[4]  D. Veale,et al.  Notch‐1 mediates endothelial cell activation and invasion in psoriasis , 2014, Experimental dermatology.

[5]  S. Chang,et al.  Gene Profiling Analysis of the Early Effects of Ablative Fractional Carbon Dioxide Laser Treatment on Human Skin , 2013, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[6]  Mi-Yeon Kim,et al.  Wnt5a Controls Notch1 Signaling through CaMKII-mediated Degradation of the SMRT Corepressor Protein* , 2012, The Journal of Biological Chemistry.

[7]  M. Suárez-Fariñas,et al.  Resolved psoriasis lesions retain expression of a subset of disease-related genes. , 2011, The Journal of investigative dermatology.

[8]  James T. Elder,et al.  Evidence for altered Wnt signaling in psoriatic skin. , 2010, The Journal of investigative dermatology.

[9]  Frank O. Nestle,et al.  Mechanisms of Disease: Psoriasis. , 2009 .

[10]  M. Katoh,et al.  Transcriptional mechanisms of WNT5A based on NF-κB, Hedgehog, TGFβ, and Notch signaling cascades , 2009 .

[11]  S. Bray,et al.  Wnt5a Exhibits Layer-Specific Expression in Adult Skin, Is Upregulated in Psoriasis, and Synergizes with Type 1 Interferon , 2009, PloS one.

[12]  R. Nusse,et al.  Alternative Wnt Signaling Is Initiated by Distinct Receptors , 2008, Science Signaling.

[13]  H. Tagami,et al.  Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. , 2008, Journal of dermatological science.

[14]  M. Kurrer,et al.  Wnt5A/CaMKII Signaling Contributes to the Inflammatory Response of Macrophages and Is a Target for the Antiinflammatory Action of Activated Protein C and Interleukin-10 , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[15]  D. Charnock-Jones,et al.  Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration. , 2008, Biochemical and biophysical research communications.

[16]  I. Nishimoto,et al.  Wnt5a promotes adhesion of human dermal fibroblasts by triggering a phosphatidylinositol-3 kinase/Akt signal. , 2007, Cellular signalling.

[17]  A. Zeiher,et al.  Notch Signaling Contributes to the Expression of Cardiac Markers in Human Circulating Progenitor Cells , 2007, Circulation research.

[18]  Ki Wook Kim,et al.  Role of Wnt5a in the proliferation of human glioblastoma cells. , 2007, Cancer letters.

[19]  M. Obinata,et al.  p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity , 2007, Oncogene.

[20]  J. Garlick,et al.  Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. , 2007, Genes & development.

[21]  B. Tycko,et al.  Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. , 2006, Molecular biology of the cell.

[22]  Holger Heine,et al.  The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. , 2006, Blood.

[23]  Jian Wang,et al.  Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. , 2006, Genes & development.

[24]  C. Brisken,et al.  Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  B. Villoutreix,et al.  A Formylated Hexapeptide Ligand Mimics the Ability of Wnt-5a to Impair Migration of Human Breast Epithelial Cells* , 2006, Journal of Biological Chemistry.

[26]  Vikram Devgan,et al.  p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. , 2005, Genes & development.

[27]  J. Neilson,et al.  Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. , 2005, Developmental cell.

[28]  D. Ball,et al.  Notch in lung development and lung cancer. , 2004, Seminars in cancer biology.

[29]  A. Ishida-Yamamoto,et al.  Unique Keratinization Process in Psoriasis: Late Differentiation Markers Are Abolished Because of the Premature Cell Death , 2004, The Journal of dermatology.

[30]  G. Dotto,et al.  High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. , 2004, Developmental cell.

[31]  Eric C. Lai,et al.  Notch signaling: control of cell communication and cell fate , 2004, Development.

[32]  Wing Hung Wong,et al.  Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. , 2003, Physiological genomics.

[33]  Hans Clevers,et al.  Notch1 functions as a tumor suppressor in mouse skin , 2003, Nature Genetics.

[34]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-κB and PPARγ , 2002, Cell Death and Differentiation.

[35]  J. Thélu,et al.  Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing , 2002, BMC dermatology.

[36]  Freddy Radtke,et al.  Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation , 2001, The EMBO journal.

[37]  S. Artavanis-Tsakonas,et al.  Intracellular Cleavage of Notch Leads to a Heterodimeric Receptor on the Plasma Membrane , 1997, Cell.

[38]  A. M. Arias,et al.  Notch is required for wingless signaling in the epidermis of Drosophila , 1994, Cell.

[39]  M. Katoh,et al.  Transcriptional mechanisms of WNT5A based on NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades. , 2009, International journal of molecular medicine.

[40]  Joachim Reischl,et al.  Increased expression of Wnt5a in psoriatic plaques. , 2007, The Journal of investigative dermatology.

[41]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. , 2002, Cell death and differentiation.