Altered epidermal proliferation, differentiation, and lipid composition: Novel key elements in the vitiligo puzzle

Abstract

Vitiligo is an acquired skin depigmentation disease involving multiple pathogenetic mechanisms, which ultimately direct cytotoxic CD8 + cells to destroy melanocytes. Abnormalities have been described in several cells even in pigmented skin as an expression of a functional inherited defect. Keratinocytes regulate skin homeostasis by the assembly of a proper skin barrier and releasing and responding to cytokines and growth factors. Alterations in epidermal proliferation, differentiation, and lipid composition as triggers for immune response activation in vitiligo have not yet been investigated. By applying cellular and lipidomic approaches, we revealed a deregulated keratinocyte differentiation with altered lipid composition, associated with impaired energy metabolism and increased glycolytic enzyme expression. Vitiligo keratinocytes secreted inflammatory mediators, which further increased following mild mechanical stress, thus evidencing immune activation. These findings identify intrinsic alterations of the nonlesional epidermis, which can be the prime instigator of the local inflammatory milieu that stimulates immune responses targeting melanocytes.

A Possible Modulator of Vitiligo Metabolic Impairment: Rethinking a PPARγ Agonist

“…Among the various pathogenetic hypotheses, our research has been particularly effective in the explanation of non-immunological factors, demonstrating the presence of metabolic impairment in almost all epidermal cells [ 5 , 7 ]. In accordance with our data, vitiligo could be defined as a mitochondrial disease leading to an aging phenomenon and to an alteration of the skin barrier, which could be an initial event in the development of the inflammatory process [ 5 , 6 , 8 , 38 ]. The regulation of energy metabolism is critical in maintaining intracellular redox equilibrium, strictly related to mitochondria efficiency.…”

“…Accordingly, PGZ reduces the expression of chemokine receptor CXCR3B, decreases the release of several DAMPs as well as, HMGB1 and Hsp70, and significantly lowers the gene expression levels of MICA and MICB. During the last years, our group reported that metabolic abnormalities are common to the entire vitiligo skin [ 7 , 8 ]. Starting from these considerations, we assayed that, in fibroblasts isolated from vitiligo patients, PGZ affected the release of growth factors and improved the production of extracellular components, such as Fibronectin.…”

“…Recently, our group has shown that some of the described alterations are not exclusive to melanocytes but can be observed in other skin cells obtained from pigmented areas, suggesting that vitiligo leads to the degeneration of the entire skin [ 7 , 8 ]. Fibroblasts exhibit oxidative stress, overexpression of p53, and a senescent phenotype [ 7 ].…”

“…These features are the basis for the altered secretion of soluble growth factors supporting melanocyte survival and homeostasis. The consequent alteration of the dermal-epidermal network could be the basis for melanocyte detachment [ 7 , 8 , 9 ]. Moreover, our group recently demonstrated abnormalities in the keratinocyte differentiation process and consequently an inappropriate assembly of the epidermal layers which, following stressful events, can induce an inflammatory reaction capable of activating an immune response targeting melanocytes [ 8 ].…”

“…The consequent alteration of the dermal-epidermal network could be the basis for melanocyte detachment [ 7 , 8 , 9 ]. Moreover, our group recently demonstrated abnormalities in the keratinocyte differentiation process and consequently an inappropriate assembly of the epidermal layers which, following stressful events, can induce an inflammatory reaction capable of activating an immune response targeting melanocytes [ 8 ]. These findings further strengthen the pivotal role of metabolic alterations in vitiligo onset and development.…”