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Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.

Skin fibrosis is the result of aberrant processes leading to abnormal deposition of extracellular matrix (ECM) in the dermis. In healthy skin, keratinocytes participate to maintain skin homeostasis by actively crosstalking with fibroblasts. Within the wide spectrum of fibrotic skin disorders, relatively little attention has been devoted to the role of keratinocytes for their capacity to participate to skin fibrosis. This systematic review aims at summarizing the available knowledge on the reciprocal interplay of keratinocytes with fibroblasts and their soluble mediators in physiological states, mostly wound healing, and conditions associated with skin fibrosis. We performed a systematic literature search on PubMed to identify human studies investigating the keratinocyte characteristics and their interplay with fibroblasts in physiological conditions and within fibrotic skin disorders including hypertrophic scars, keloids, and systemic sclerosis. Studies were selected according to pre-specified eligibility criteria. Data on study methods, models, stimuli and outcomes were retrieved and summarized according to pre-specified criteria. Among the 6,271 abstracts retrieved, 73 articles were included, of which 14 were specifically dealing with fibrotic skin pathologies. Fifty-six studies investigated how keratinocyte may affect fibroblast responses in terms of ECM-related genes or protein production, phenotype modification, and cytokine production. Most studies in both physiological conditions and fibrosis demonstrated that keratinocytes stimulate fibroblasts through the production of interleukin 1, inducing keratinocyte growth factor (KGF) and metalloproteinases in the fibroblasts. When the potential of keratinocytes to modulate collagen synthesis by healthy fibroblasts was explored, the results were controversial. Nevertheless, studies investigating keratinocytes from fibrotic skin, including keloids, hypertrophic scar, and scleroderma, suggested their potential involvement in enhancing ECM deposition. Twenty-three papers investigated keratinocyte proliferation differentiation and production of soluble mediators in response to interactions with fibroblasts. Most studies showed that fibroblasts modulate keratinocyte viability, proliferation, and differentiation. The production of KGF by fibroblast was identified as key for these functions. This review condenses evidence for the active interaction between keratinocytes and fibroblasts in maintaining skin homeostasis and the altered homeostatic interplay between keratinocytes and dermal fibroblasts in scleroderma and scleroderma-like disorders.

Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne. Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here the authors show that GATA6 is involved in maintaining homeostasis of the upper pilosebaceous unit of human skin and may contribute to acne pathogenesis.

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies. Autologous transgenic epidermal stem cell cultures are used to reconstitute almost the entire epidermis of a patient with severe junctional epidermolysis bullosa. Stem cells regenerate skin Patients with junctional epidermolysis bullosa (JEB) carry mutations in genes that encode components of the basement membrane, which ensures the integrity between the epidermis and the dermis, such as laminin-332. These mutations cause blistering of the skin and chronic wounds. Following initial treatment of an adult patient with a limited affected region, Michele De Luca and colleagues reconstruct the full epidermis of a 7-year-old patient with autologous transgenic cells transduced with a virus vector carrying the non-mutated form of laminin-322. The integration sites of the virus used for gene delivery provide a tracing tool ex vivo and in vivo and demonstrate that the human epidermis is sustained by a limited number of long-lived stem cells.

Skin exposure to ultraviolet radiation (UVR) causes oxidative stress, inflammation, and collagen degradation and can trigger erythema. While topical formulas protect the skin from UV damage, there is growing evidence that certain botanical ingredients taken orally may have an added benefit. This study evaluated the photoprotective, anti-photoaging, and anti-erythema efficacy of a combination of rosemary and grapefruit extract (Nutroxsun®). Radical oxygen species (ROS) generation and interleukin production were determined in UV-irradiated keratinocytes (HaCaT). Also, collagen and elastin secretion and metalloproteinase (MMP-1 and MMP-3) content were assessed in UV-irradiated fibroblasts (NHDFs). Furthermore, a placebo-controlled, randomized, crossover study was conducted in 20 subjects (phototypes I to III) receiving two doses, 100 and 200 mg, of the ingredient. Skin redness (a* value, CIELab) after exposure to one minimal erythemal dose of UVR was assessed. As a result, the botanical blend significantly attenuated the UVR-induced reductions of procollagen I and elastin and lowered MMP-1 and MMP-3 protein secretion. Also, a reduction in ROS and proinflammatory interleukins (IL-1, IL-8, and IL-6) was observed. Finally, the botanical blend, at both doses, significantly reduced UV-induced erythema reaction from the first day of intake and accelerated recovery. These findings reinforce the potential of this ingredient as an effective dietary solution to protect the skin against UV-induced damage.

As the most dominant cell type in the skin, keratinocytes play critical roles in wound repair not only as structural cells but also exerting important immune functions. This review focuses on the communications between keratinocytes and immune cells in wound healing, which are mediated by various cytokines, chemokines, and extracellular vesicles. Keratinocytes can also directly interact with T cells via antigen presentation. Moreover, keratinocytes produce antimicrobial peptides that can directly kill the invading pathogens and contribute to wound repair in many aspects. We also reviewed the epigenetic mechanisms known to regulate keratinocyte immune functions, including histone modifications, non-protein-coding RNAs (e.g., microRNAs, and long noncoding RNAs), and chromatin dynamics. Lastly, we summarized the current evidence on the dysregulated immune functions of keratinocytes in chronic nonhealing wounds. Based on their crucial immune functions in skin wound healing, we propose that keratinocytes significantly contribute to the pathogenesis of chronic wound inflammation. We hope this review will trigger an interest in investigating the immune roles of keratinocytes in chronic wound pathology, which may open up new avenues for developing innovative wound treatments.

AHAs are organic acids with one hydroxyl group attached to the alpha position of the acid. AHAs including glycolic acid, lactic acid, malic acid, tartaric acid, and citric acid are often used extensively in cosmetic formulations. AHAs have been used as superficial peeling agents as well as to ameliorate the appearance of keratoses and acne in dermatology. However, caution should be exercised in relation to certain adverse reactions among patients using products with AHAs, including swelling, burning, and pruritus. Whether AHAs enhance or decrease photo damage of the skin remains unclear, compelling us to ask the question, is AHA a friend or a foe of the skin? The aim of this manuscript is to review the various biological effects and mechanisms of AHAs on human keratinocytes and in an animal model. We conclude that whether AHA is a friend or foe of human skin depends on its concentration. These mechanisms of AHAs are currently well understood, aiding the development of novel approaches for the prevention of UV-induced skin damage.

Heat shock proteins (HSPs), a large group of highly evolutionary conserved proteins, are considered to be main elements of the cellular proteoprotection system. HSPs are encoded by genes activated during the exposure of cells to proteotoxic factors, as well as by genes that are expressed constitutively under physiological conditions. HSPs, having properties of molecular chaperones, are involved in controlling/modulation of multiple cellular and physiological processes. In the presented review, we summarize the current knowledge on HSPs in the biology of epidermis, the outer skin layer composed of stratified squamous epithelium. This tissue has a vital barrier function preventing from dehydratation due to passive diffusion of water out of the skin, and protecting from infection and other environmental insults. We focused on HSPB1 (HSP27), HSPA1 (HSP70), HSPA2, and HSPC (HSP90), because only these HSPs have been studied in the context of physiology and pathophysiology of the epidermis. The analysis of literature data shows that HSPB1 plays a role in the regulation of final steps of keratinization; HSPA1 is involved in the cytoprotection, HSPA2 contributes to the early steps of keratinocyte differentiation, while HSPC is essential in the reepithelialization process. Since HSPs have diverse functions in various types of somatic tissues, in spite of multiple investigations, open questions still remain about detailed roles of a particular HSP isoform in the biology of epidermal keratinocytes.

Background Skin aging is one of the most abundant aging‐related disorders that can be accelerated by excessive exposure to ultraviolet irradiation. Topically applied fermented skincare ingredients have gained mounting attentions due to their high concentration of various skin nourishing nutrients and bioactive components and low skin irritation potency. Aims In the present study, we aim to fully demonstrate the skin‐related benefits of a novel extract of Thermus thermophilus and Bacillus subtilis mixed‐culture ferment (TBFE). Methods TBFE was prepared through an innovative mixed‐culture fermentation process. The contents of nutrients and bioactive ingredients were quantified by different methods accordingly. Both in vitro tests and randomized controlled human trial were utilized to further demonstrate multifaceted beneficial effects on human skin, as well as the potential mechanisms. Results Our results showed that TBFE upregulated the expression of type IV collagen, elastin, aquaporin‐3, and dermal‐epidermal junction markers, while inhibited production of melanin, in different skin cell models. Moreover, TBFE inhibited the generation of reactive oxygen species and pro‐inflammatory mediators induced by ultraviolet irradiation in normal human keratinocytes, while stimulated autophagy in senescent keratinocytes. Results from clinical studies confirmed those in vitro findings, demonstrating that TBFE at 5% and 20% concentration provides anti‐aging properties in subjects with sensitive skin, in terms of improving wrinkles, moisturization, and skin lightening. Conclusions In summary, we demonstrate that a novel mixed‐culture ferment extract has promising anti‐aging effects, which may be attributed to anti‐oxidation, anti‐inflammation, and promotion of autophagy in skin cells.

Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFα or IL-1β. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti-inflammatory interventions/therapies on skin diseases.