Post-Inflammatory Hyperpigmentation in Dark Skin: Molecular Mechanism and Skincare Implications.

Human skin is characterized by significant diversity in color and tone, which are determined by the quantity and distribution of melanin pigment in the epidermis. Melanin absorbs and reflects ultraviolet radiation (UVR), preventing the damage to genomic DNA in the epidermis and degradation of collagen in the dermis; therefore, darker skin types are thought to be well protected from the photodamage because of the high melanin content. However, increased content of melanin in combination with the extrinsic stress factors causing inflammation such as excess UVR, allergic reactions, or injury can also frequently lead to cosmetic problems resulting in discoloration and scarring. This review summarizes current knowledge on histopathology and likely molecular signatures of one of the most common problems, post-inflammatory hyperpigmentation (PIH). The mechanisms proposed so far are subsequently discussed in the context of other factors characterizing darker skin types. This includes the common cellular features, organization of upper skin layers, and major biomarkers, with particular emphasis on increased propensities to systemic and localized inflammation. Enhanced or prolonged inflammatory responses can not only affect the process of melanogenesis but also have been implicated in injury-related skin pathologies and aging. Finally, we summarize the major cosmetic treatments for PIH and their known anti-inflammatory targets, which can be beneficial for darker skin tones and combined with broad-spectrum filters against UVR.

Omeprazole, a gastric proton pump inhibitor, inhibits melanogenesis by blocking ATP7A trafficking.

Omeprazole is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking ATP4A, a P-type H+/K+ ATPase in gastric parietal cells. We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells, normal human epidermal melanocytes, and in a reconstructed human skin model. Omeprazole topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls. Omeprazole had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase, dopachrome tautomerase, Pmel17, or MITF mRNA levels. Although melanocytes do not express ATP4A, they do express ATP7A, a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase. ATP7A relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole. Omeprazole treatment increased the proportion of EndoH sensitive tyrosinase, indicating that tyrosinase maturation was impaired. In addition, omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide, suggestive of increased degradation. Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting ATP7A and by enhancing degradation of tyrosinase.

Skin cells and tissue are capable of using L-ergothioneine as an integral component of their antioxidant defense system.

The cellular defense system against harmful levels of reactive oxygen species consists of antioxidant enzymatic activities and small nonenzymatic molecules. L-ergothioneine has long been recognized as a potent and stable low-molecular-weight antioxidant that humans consume with diet and that accumulates in cells normally subjected to high levels of oxidative stress. As L-ergothioneine is plasma membrane-impermeative, its protective function is restricted to cells that express the L-ergothioneine-specific receptor/transporter OCTN1. Here we report for the first time that both as resident skin cells and in culture, epidermal keratinocytes synthesize OCTN1, which enables them to internalize and accumulate L-ergothioneine. This accumulation confers upon the cells an increased antioxidant potential. Consequently, it reduces the levels of reactive oxygen species and DNA, protein, and lipid damage in keratinocytes subjected to solar-simulating UV oxidative stress. Our results suggest that L-ergothioneine not only prevents oxidative damage but also may enable DNA repair in the UV-irradiated cells. The diminished oxidative damage to cellular constituents limits the apoptotic response and results in increased cell viability. The cells' ability to take up, accumulate, and utilize the potent antioxidant L-ergothioneine positions this naturally occurring amino acid and its receptor/transporter as an integral part of the antioxidative defense system of the skin.

Inhibition of histone deacetylation promotes abnormal epidermal differentiation and specifically suppresses the expression of the late differentiation marker profilaggrin.

Reversible protein acetylation modulates higher-order chromatin structure and transcription activity of the genome. The reversible acetylation is executed by the intrinsic acetylase and deacetylase activities of co-regulators associated with the regulatory regions. Compounds capable of inhibiting deacetylase activity are a powerful tool for dissecting the role of protein acetylation in gene function. The ability of the deacetylase inhibitors to preferentially affect the homeostasis of transformed cells has also prompted studies for their clinical application. We present evidence that deacetylase inhibition with trichostatin A (TSA) affects the normal epidermal tissue architecture and pattern of expression by a mechanism(s) that does not correlate directly with the hyperacetylated histone status. While promoting abnormal differentiation, TSA specifically represses transcription initiation of the differentiation marker profilaggrin. Multiple factors, among which we have identified decreased Sp1 binding, a local decrease in acetylation activity, and enhanced synthesis and recruitment of a repressor histone demethylase, alter the chromatin configuration over the promoter, ultimately blocking its activation by c-jun. As compromised profilaggrin production leads to epidermal and consequently allergic disorders, our findings emphasize the need for a detailed investigation of the role deacetylase inhibitors may play in the maintenance of epidermal homeostasis in order to optimize their clinical applicability.

Expression of truncated latent TGF-beta-binding protein modulates TGF-beta signaling.

Transforming growth factor-beta is released from most cells as an inactive complex consisting of transforming growth factor-beta, the transforming growth factor-beta propeptide and the latent transforming growth factor-beta-binding protein. We studied the role of latent transforming growth factor-beta-binding protein in modulating transforming growth factor-beta availability by generating transgenic mice that express a truncated form of latent transforming growth factor-beta-binding protein-1 that binds to transforming growth factor-beta but is missing the known N- and C-terminal matrix-binding sequences. As transforming growth factor-beta is an inhibitor of keratinocyte proliferation and is involved in the control of hair cycling, we over-expressed the mutated form of latent transforming growth factor-beta-binding protein under the control of the keratin 14-promoter. Transgenic animals displayed a hair phenotype due to a reduction in keratinocyte proliferation, an abbreviated growth phase and an early initiation of the involution (catagen) phase of the hair cycle. This phenotype appears to result from excess active transforming growth factor-beta, as enhanced numbers of pSmad2/3-positive nuclei are observed in transgenic animal skin. These data suggest that the truncated form of latent transforming growth factor-beta-binding protein-1 competes with wild-type latent transforming growth factor-beta-binding protein for binding to latent transforming growth factor-beta, resulting in latent transforming growth factor-beta complexes that fail to be targeted correctly in the extracellular matrix. The mis-localization of the transforming growth factor-beta results in inappropriate activation and premature initiation of catagen, thereby illustrating the significance of latent transforming growth factor-beta-binding protein interaction with transforming growth factor-beta in the targeting and activation of latent transforming growth factor-beta in addition to previously reported effects on small latent complex secretion.