Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

Abstract

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.

Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

“…The observations that Dsg1 loss in utero is sufficient to stimulate a Th17 skewed inflammatory response and Dsg1's unique sensitivity to loss via extrinsic stressors, suggest that Dsg1 loss may activate a protective response. This is consistent with our recent findings that UV exposure selectively downregulates Dsg1, and conditioned media from Dsg1deficient keratinocytes stimulates increased melanin secretion in primary melanocytes, a protective response to UV exposure (16,17).…”

“…Intermediate filament anchoring desmosomes appeared during evolution around the time that adaptive immunity developed in jawless fish, and the keratinocyte specific desmosomal cadherin Dsg1 appeared even later when vertebrates became terrestrial and required a barrier suited to a new environment (18). We recently proposed the idea that this "newest" desmosomal cadherin acts as a sensor of environmental stress by remodeling the secretome upon stress-induced down-regulation of Dsg1 (16,18). Supporting this, chronic loss of Dsg1, as occurs in SAM syndrome, is associated with chronic inflammatory and allergic disease.…”

“…While the loss of barrier forming roles of Dsg1 may contribute to these symptoms, isolated patient keratinocytes exhibit cell autonomous production of cytokines, including the pro-allergic cytokines thymic stromal lymphopoietin (TSLP), IL-5 and tumor necrosis factor (TNF) (10,14). Further, knockdown of Dsg1 in normal human keratinocytes in vitro was sufficient to induce the expression of pro-inflammatory cytokines IL-1b, CXCL1 and TNF (14,16). Combined with the observation that Dsg1 is downregulated in response to environmental stress, such as exposure to UV, these observations raise the possibility that Dsg1 is a stress sensor that governs the expression of cytokines independently of its role in maintaining tissue integrity and barrier function (10,(16)(17)(18).…”

“…Further, knockdown of Dsg1 in normal human keratinocytes in vitro was sufficient to induce the expression of pro-inflammatory cytokines IL-1b, CXCL1 and TNF (14,16). Combined with the observation that Dsg1 is downregulated in response to environmental stress, such as exposure to UV, these observations raise the possibility that Dsg1 is a stress sensor that governs the expression of cytokines independently of its role in maintaining tissue integrity and barrier function (10,(16)(17)(18).…”

Comprehensive analysis and identification of key genes and signaling pathways in the occurrence and metastasis of cutaneous melanoma

“…This process increased the aggressiveness of the tumor by the loss of the epithelial phenotype (E-cadherin, desmosin, laminin-1) and the acquisition of the mesenchymal marker (N-cadherin) (Kalluri & Robert, 2009). Hub gene desmoglein1(DSG1) could control the role of keratinocytes, and contribute to the page-like behavior in the development of melanoma (Arnette et al, 2020). Furthermore, desmocollin1(DSC1) and desmocollin3(DSC3) are members of the E-cadherin superfamily, involved in cell-cell adhesion and cell-extracellular matrix interaction.…”