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

Abstract

BackgroundPsoriasis 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.ObjectiveWe aimed to investigate the interaction of Wnt5a with Notch 1 with respect to inflammation-mediated epidermal hyperproliferation in psoriasis.MethodsExpression 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).ResultsIn 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.ConclusionOur data suggest that Wnt5a and Notch1 signaling exert counteracting influences on each other and are involved, in part, in the pathomechanism of psoriasis.

Integrative analyses reveal biological pathways and key genes in psoriasis

“…FZD2 and FZD5 , which encode receptors for WNT5A , are also upregulated. Increased WNT5A expression induces the proliferation of keratinocytes and adhesion of fibroblasts . Moreover, WNT5A induces inflammatory responses and innate immunity .…”

The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond

“…These findings suggest that Wnt5a plays an important regulatory role during the host response to M. tuberculosis infection by activating innate immune cells, which in turn directly affects adaptive immune cell function. However, Wnt5a expression and its pro-inflammatory activity have also been linked to the pathogenesis of multiple chronic inflammatory diseases, including rheumatoid arthritis (66), psoriasis (73), colitis (69), atherosclerosis (74–76), and obesity (56, 57). With regard to TB, however, it remains elusive whether excessive Wnt5a formation may contribute to the M. tuberculosis -induced immunopathology.…”

Beta‐catenin non‐canonical pathway: A potential target for inflammatory and hyperproliferative state via expression of transglutaminase 2 in psoriatic skin keratinocyte

“…59 and TNF-α and interferon-γ stimulated the keratinocytes to higher Wnt5a levels, blocking Notch1 and HES1 in turn. 65 In contrast to specific reports, Wnt5a has pro-inflammatory activity in monocytes/macrophages. 57 The previous study, explaining two cytokines IL-6 and TNF-α, which are widely accepted systemic inflammatory markers and modulated by JnK-dependent Wnt5a.…”

“…The effect of Wnt5a on keratinocytes was also determined by a series of in vitro experiments. Recombinant Wnt5a therapy improved the proliferation and secretion of human keratinocytes of IL‐1α, IL‐12, IL‐23, and TNF‐α and interferon‐γ stimulated the keratinocytes to higher Wnt5a levels, blocking Notch1 and HES1 in turn 65 . In contrast to specific reports, Wnt5a has pro‐inflammatory activity in monocytes/macrophages 57 .…”