Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes

Mao, Xuming; Cho, Michael Jeffrey T; Ellebrecht, Christoph T.; Mukherjee, Eric M.; Payne, Aimee

doi:10.1172/jci.insight.92253

Cited by 21 publications

(11 citation statements)

References 34 publications

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“…Histone deacetylase (HDAC) inhibition using TSA was shown to moderately increase KC Dsg1 levels after UVB exposure (Johnson et al, ). Other desmogleins are being regulated through the use of glucocorticoids, rapamycin, and Stat3 inhibition in the treatment of pemphigus (Mao, Cho, Ellebrecht, Mukherjee, & Payne, ).…”

Section: Discussionmentioning

confidence: 99%

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

Arnette

Roth-Carter

Koetsier

et al. 2019

Pigment Cell Melanoma Res

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The epidermis is the first line of defense against ultraviolet (UV) light from the sun. Keratinocytes and melanocytes respond to UV exposure by eliciting a tanning response dependent in part on paracrine signaling, but how keratinocyte:melanocyte communication is regulated during this response remains understudied. Here, we uncover a surprising new function for the keratinocyte‐specific cell–cell adhesion molecule desmoglein 1 (Dsg1) in regulating keratinocyte:melanocyte paracrine signaling to promote the tanning response in the absence of UV exposure. Melanocytes within Dsg1‐silenced human skin equivalents exhibited increased pigmentation and altered dendrite morphology, phenotypes which were confirmed in 2D culture using conditioned media from Dsg1‐silenced keratinocytes. Dsg1‐silenced keratinocytes increased melanocyte‐stimulating hormone precursor (Pomc) and cytokine mRNA. Melanocytes cultured in media conditioned by Dsg1‐silenced keratinocytes increased Mitf and Tyrp1 mRNA, TYRP1 protein, and melanin production and secretion. Melanocytes in Dsg1‐silenced skin equivalents mislocalized suprabasally, reminiscent of early melanoma pagetoid behavior. Together with our previous report that UV reduces Dsg1 expression, these data support a role for Dsg1 in controlling keratinocyte:melanocyte paracrine communication and raise the possibility that a Dsg1‐deficient niche contributes to pagetoid behavior, such as occurs in early melanoma development.

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Section: Discussionmentioning

confidence: 99%

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

Arnette

Roth-Carter

Koetsier

et al. 2019

Pigment Cell Melanoma Res

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“…Indeed, topical p38MAPK inhibitors may represent a therapeutic strategy in pemphigus to overcome the significant toxicity observed with the systemic counterpart. Finally in a study by Mao et al (308), inhibition of STAT3 by hydrocortisone, rapamicin, an inhibitor of mTOR, or Stat3 inhibitor XVIII prevented blister formation in a passive transfer PV mouse model by up-regulating the expression of Dsg3. Interestingly, sirolimus, a systemic inhibitor of mTOR, was shown to be effective in PV, whereas topical rapamicin did not (309, 310).…”

Section: Emerging Therapiesmentioning

confidence: 97%

Pemphigus: Current and Future Therapeutic Strategies

et al. 2019

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Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.

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“…Since Dsg3 clustering was shown to be the structural correlate of Dsg3 depletion ( 11 ), these data indicate that the depletion of Dsg3 alone may be a primary mechanism in mucosal eroding but alone is not sufficient to cause epidermal blistering. Nevertheless, Dsg3 depletion may drastically worsen desmosome destabilization in the epidermis which is suggested by the fact that glucocorticoids rapidly improve the clinical phenotype ( 1 ) at least in part via Stat3-induced Dsg3 transcription increase ( 12 ).…”

Section: Histology and Ultrastructure Of Patient’s Lesions Highlight mentioning

confidence: 99%

Pemphigus—A Disease of Desmosome Dysfunction Caused by Multiple Mechanisms

Spindler

Waschke

2018

Front. Immunol.

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Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells. Autoantibodies against the desmosomal cadherins desmogleins (Dsgs) 1 and 3 as well as desmocollin 3 were shown to be pathogenic, whereas the role of other antibodies is unclear. Dsg3 interactions can be directly reduced by specific autoantibodies. Autoantibodies also alter the activity of signaling pathways, some of which regulate cell cohesion under baseline conditions and alter the turnover of desmosomal components. These pathways include Ca2+, p38MAPK, PKC, Src, EGFR/Erk, and several others. In this review, we delineate the mechanisms relevant for pemphigus pathogenesis based on the histology and the ultrastructure of patients’ lesions. We then dissect the mechanisms which can explain the ultrastructural hallmarks detectable in pemphigus patient skin. Finally, we reevaluate the concept that the spectrum of mechanisms, which induce desmosome dysfunction upon binding of pemphigus autoantibodies, finally defines the clinical phenotype.

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Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes

Cited by 21 publications

References 34 publications

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

Pemphigus: Current and Future Therapeutic Strategies

Pemphigus—A Disease of Desmosome Dysfunction Caused by Multiple Mechanisms

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