Introducing aesthetic regenerative scaffolds: An immunological perspective.

BACKGROUND: Skin aging arises from immunological responses to tissue deterioration and damage. Tissue repair processes encompass the regeneration of original tissue and 'scarless' wound healing seen in foetuses, and the extreme fibrotic responses and scarring seen in adults. Anti-aging aesthetic medicine uses interventions like biomaterial-based fillers to influence these immunological responses and renew aged tissue structure and function. At filler injection sites, an inflammatory response occurs that causes a spectrum of outcomes, ranging from tissue regeneration to fibrosis and filler encapsulation. Importantly, the resulting inflammatory pathway can be predetermined by the biomaterial injected. AIMS: By understanding this immunological process, we can develop Aesthetic Regenerative Scaffolds (ARS) - aesthetic injectable biomaterials - to direct inflammatory wound healing away from chronic, fibrotic responses, and towards physiological tissue regeneration. MATERIALS AND METHODS: We identified and reviewed literature on the immunological and cellular responses to injected dermal fillers, whereby the wound healing response to the injection was moderated under the influence of an injected biomaterial. RESULTS: We described the mechanisms of dermal wound healing and the use of ARS to direct healing towards tissue regeneration instead of scarring. We also summarised studies on extracellular matrix remodeling by calcium hydroxylapatite. We found that Calcium hydroxylapatite fillers produce collagen as they gradually degrade and their spherical structures serve as a scaffold for tissue regeneration. Furthermore, CaHA improved fibroblast contractility, collagen type III and elastin production, proliferation and angiogenesis with less inflammation than hyaluronic acid fillers. DISCUSSION: Regneration pathways can be influenced at specific points between a facial filler biomaterial and the wound healingmechanisms at its site of implantaion. CONCLUSION: Physicians can select scaffolds that direct the immune response away from a fibrotic chronic inflammatory pathway and towards regeneration to enable true repair of the aging skin.

Immunological Aspects of Skin Aging in Atopic Dermatitis.

The cutaneous immune response is important for the regulation of skin aging well as for the development of immune-mediated skin diseases. Aging of the human skin undergoes immunosenescence with immunological alterations and can be affected by environmental stressors and internal factors, thus leading to various epidermal barrier abnormalities. The dysfunctional epidermal barrier, immune dysregulation, and skin dysbiosis in the advanced age, together with the genetic factors, facilitate the late onset of atopic dermatitis (AD) in the elderly, whose cases have recently been on the rise. Controversial to the healthy aged skin, where overproduction of many cytokines is found, the levels of Th2/Th22 related cytokines inversely correlated with age in the skin of older AD patients. As opposed to an endogenously aged skin, the expression of the terminal differentiation markers significantly increases with age in AD. Despite the atenuated barrier disturbances in older AD patients, the aged skin carries an impairment associated with the aging process, which reflects the persistence of AD. The chronicity of AD in older patients might not directly affect skin aging but does not allow spontaneous remission. Thus, adult- and elderly subtypes of AD are considered as a lifelong disease.

Luteolin as a modulator of skin aging and inflammation.

Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense. Furthermore, anti-oxidative and anti-inflammatory activities of luteolin were described on keratinocytes and fibroblasts as well as on several immune cells (e.g., macrophages, mast cell, neutrophils, dendritic cells and T cells). Luteolin can suppress proinflammatory mediators (e.g., IL-1ß, IL-6, IL-8, IL-17, IL-22, TNF-α and COX-2) and regulate various signaling pathway (e.g., the NF-κB, JAK-STAT as well as TLR signaling pathway). In this way, luteolin modulates many inflammatory processes of the skin. The present review summarizes the recent in vitro and in vivo research on luteolin in the field of skin aging and skin cancer, wound healing as well as inflammatory skin diseases, including psoriasis, contact dermatitis and atopic dermatitis. In conclusion, luteolin might be a promising molecule for the development of topic formulations and systemic agents against inflammatory skin diseases.

Inflammasome Activation in Pollution-Induced Skin Conditions.

SUMMARY: Exposure to air pollutants has been now associated with detrimental effects on a variety of organs, including the heart, lungs, GI tract, and brain. However, recently it has become clear that pollutant exposure can also promote the development/exacerbation of a variety of skin conditions, including premature aging, psoriasis, acne, and atopic dermatitis. Although the molecular mechanisms by which pollutant exposure results in these cutaneous pathological manifestations, it has been noticed that an inflammatory status is a common denominator of all those skin conditions. For this reason, recently, the activation of a cytosolic multiprotein complex involved in inflammatory responses (the inflammasome) that could promote the maturation of proinflammatory cytokines interleukin-1ß and interleukin-18 has been hypothesized to play a key role in pollution-induced skin damage. In this review, we summarize and propose the cutaneous inflammasome as a novel target of pollutant exposure and the eventual usage of inflammasome inhibitor as new technologies to counteract pollution-induced skin damage. Possibly, the ability to inhibit the inflammasome activation could prevent cutaneous inflammaging and ameliorate the health and appearance of the skin.

Epilipidomics of Senescent Dermal Fibroblasts Identify Lysophosphatidylcholines as Pleiotropic Senescence-Associated Secretory Phenotype (SASP) Factors.

During aging, skin accumulates senescent cells. The transient presence of senescent cells, followed by their clearance by the immune system, is important in tissue repair and homeostasis. The persistence of senescent cells that evade clearance contributes to the age-related deterioration of the skin. The senescence-associated secretory phenotype of these cells contains immunomodulatory molecules that facilitate clearance but also promote chronic damage. Here, we investigated the epilipidome-the oxidative modifications of phospholipids-of senescent dermal fibroblasts, because these molecules are among the bioactive lipids that were recently identified as senescence-associated secretory phenotype factors. Using replicative- and stress- induced senescence protocols, we identified lysophosphatidylcholines as universally elevated in senescent fibroblasts, whereas other oxidized lipids displayed a pattern that was characteristic for the used senescence protocol. When we tested the lysophosphatidylcholines for senescence-associated secretory phenotype activity, we found that they elicit chemokine release in nonsenescent fibroblasts but also interfere with toll-like receptor 2 and 6/CD36 signaling and phagocytic capacity in macrophages. Using matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry imaging, we localized two lysophosphatidylcholine species in aged skin. This suggests that lysophospholipids may facilitate immune evasion and low-grade chronic inflammation in skin aging.

Inflammaging and the Skin.

As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.

The Role of Platelet Homeostasis in a Novel Topical PRP Formulation.

BACKGROUND: Topical platelet-rich plasma (PRP) must demonstrate stability to insure biologic activity in aesthetic medicine. OBJECTIVE: The objective of this research was to evaluate the role of platelet homeostasis in a novel PRP topical cosmetic formulation to provide facial appearance improvement. METHODS: The stability of the topical PRP formulation was evaluated in vitro followed by clinical in vivo testing. The in vitro evaluation examined platelet stability and morphology over a 90-day period within the preservative cosmetic base utilizing ELISA and light microscopy (LM)/scanning electron microscopy (SEM). The in vivo clinical study enrolled 20 subjects in a 120-day double blind split face study to evaluate the effect of 5–7x concentrated PRP compared to 2–3x concentrated PRP on facial photoaging. Cosmetic effect was evaluated by the subject and the dermatologist investigator on a 5-point ordinal scale at baseline, week 8, and week 16. RESULTS: 90-day stability for the topical PRP formulation was verified via ELISA and LM/SEM. ELISA showed the PRP was more inactive than control conditions via analyte concentration curves (PDGF-AB, EGF, and P-Selectin). LM/SEM demonstrated the PRP had less aggregation/activation over time within the cosmetic base and that refrigeration is superior to room-temperature storage thus delaying full platelet degranulation. The in vivo clinical study demonstrated parity between 20ml and 60ml PRP in terms of clinical efficacy. CONCLUSION: Platelets remain viable for up to 90 days in a refrigerated cosmetic vehicle with demonstrated topical clinical PRP facial benefits. PRP kits of 20ml and 60ml volumes for topical PRP are equally efficacious. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5495.

Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin.

Rationale: Many external factors can induce the melanogenesis and inflammation of the skin. Salidroside (SAL) is the main active ingredient of Rhodiola, which is a perennial grass plant of the Family Crassulaceae. This study evaluated the effect and molecular mechanism of SAL on skin inflammation and melanin production. It then explored the molecular mechanism of melanin production under ultraviolet (UV) and inflammatory stimulation. Methods: VISIA skin analysis imaging system and DermaLab instruments were used to detect the melanin reduction and skin brightness improvement rate of the volunteers. UV-treated Kunming mice were used to detect the effect of SAL on skin inflammation and melanin production. Molecular docking and Biacore were used to verify the target of SAL. Immunofluorescence, luciferase reporter assay, CO-IP, pull-down, Western blot, proximity ligation assay (PLA), and qPCR were used to investigate the molecular mechanism by which SAL regulates skin inflammation and melanin production. Results: SAL can inhibit the inflammation and melanin production of the volunteers. SAL also exerted a protective effect on the UV-treated Kunming mice. SAL can inhibit the tyrosinase (TYR) activity and TYR mRNA expression in A375 cells. SAL can also regulate the ubiquitination degradation of interferon regulatory factor 1 (IRF1) by targeting prolyl 4-hydroxylase beta polypeptide (P4HB) to mediate inflammation and melanin production. This study also revealed that IRF1 and upstream stimulatory factor 1 (USF1) can form a transcription complex to regulate TYR mRNA expression. IRF1 also mediated inflammatory reaction and TYR expression under UV- and lipopolysaccharide-induced conditions. Moreover, SAL derivative SAL-plus (1-(3,5-dihydroxyphenyl) ethyl-ß-d-glucoside) showed better effect on inflammation and melanin production than SAL. Conclusion: SAL can inhibit the inflammation and melanogenesis of the skin by targeting P4HB and regulating the formation of the IRF1/USF1 transcription complex. In addition, SAL-plus may be a new melanin production and inflammatory inhibitor.

Biological Effects of Hyaluronic Acid-Based Dermal Fillers and Laser Therapy on Human Skin Models.

Injection of dermal fillers is one of the most frequently performed aesthetic procedures. The aim of the present study was to investigate the biological effects of different stabilized hyaluronan (HA) and poly-l-lactic acid fillers with and without subsequent additional fractional laser co-treatment on skin morphology and gene expression. Intradermal injection resulted in a significant enhancement of epidermal thickness detected by histological analysis. Combining HA fillers with ablative fractional CO2- or Er:YAG laser irradiation enhanced this effect. Gene expression profiling revealed an upregulation of modulators of tissue remodeling (eg TIMP3, SERPIN E1) and collagens (COL11A1). On the other hand, we detected a downregulation of differentiation markers (eg FLG, LOR, KRT1) and proinflammatory cytokines (eg IL-36, IL-1β). Interestingly, HA-based fillers revealed a specific upregulation pattern of chemokines such as CXCL5 andCCL20 suggesting a secondary effect of these fillers on the immune cells of the skin, especially monocytes and macrophages. Taken together, our data show enhancing effects of dermal fillers on epidermal thickness and prove the proliferating effects of these products on epidermal cells on the molecular level. Moreover, our findings reveal synergistic effects of fractional ablative laser treatment and HA dermal filler injection suggesting a combination of both treatments. J Drugs Dermatol. 2020;19(9):897-899. doi:10.36849/JDD.2020.4856.

A Zingerone Analog, Acetyl Zingerone, Bolsters Matrisome Synthesis, Inhibits Matrix Metallopeptidases, and Represses IL-17A Target Gene Expression.

Zingerone (Z) is a phenolic alkanone derived from natural sources with anti-inflammatory and antioxidant effects. Acetyl zingerone (AZ) is a recently designed molecule that shares structural features with Z but is expected to have improved stability and antioxidant function. This study utilized microarrays to compare the effects of Z and AZ on gene expression in reconstituted human epidermis. Both Z and AZ increased Notch pathway gene expression (NOTCH1 and MAML3) and decreased expression of genes linked to extracellular matrix disassembly (MMP3 and CTSV) and reactive oxygen species metabolism (PMAIP1 and ARG2). Although Z and AZ each inhibited in vitro matrix metallopeptidase (MMP)-1, MMP-3, and MMP-12 activity, inhibition of MMP-3 and MMP-12 was greater with AZ. Moreover, AZ led to more consistent increases in the expression of genes encoding collagens (COL11A2), proteoglycans (VCAN), and extracellular matrix glycoproteins (SPARC). Finally, AZ opposed gene expression patterns associated with fibroblast senescence, keratinocyte differentiation, and IL-17A stimulation. These effects were AZ-specific and not replicated by Z. These results show that AZ improves extracellular matrix integrity with retinoid-like effects on differentiation and inflammation. Our findings provide a rationale for clinical studies to understand the benefits of AZ in the treatment or prevention of skin aging, or potentially, as a treatment for other human skin diseases.

Interaction between low-level laser therapy and Guarana (Paullinia cupana) extract induces antioxidant, anti-inflammatory, and anti-apoptotic effects and promotes proliferation in dermal fibroblasts.

BACKGROUND: Low-level laser therapy (LLLT) has several clinical applications; however, its benefits are not universal. Therefore, combination therapy with LLLT and extracts from the guarana (Paullinia cupana) plant may improve its effectiveness as guarana extracts exhibit anti-aging properties. OBJECTIVES: To evaluate the antioxidant, anti-inflammatory, anti-apoptotic, and proliferative effects of combined LLLT and guarana extract therapy on human dermal fibroblasts. METHODS: Human dermal fibroblasts (HFF-1) were cultured and initially exposed to several concentrations (1, 3, 5, 10, 30 µg/mL) of guarana extract. The experimental concentration of guarana extract was selected by analyzing cytokine levels, DNA oxidation, and apoptotic markers in LLLT-exposed (4 J/cm2 ) and LLLT-unexposed fibroblast cultures. After 72 hours, the cells were analyzed using spectrophotometric, fluorimetric, immunological, and gene expression (qRT-PCR) assays. Flow cytometry was used to evaluate the effect of each treatment on cell cycle. RESULTS: Fibroblasts treated with guarana (5 µg/mL) exhibited anti-inflammatory and anti-apoptotic properties been used in complementary protocols. Combined guarana and LLLT treatment significantly decreased protein carbonylation, lipoperoxidation, and DNA oxidation, downregulated the mRNA and protein expression of pro-inflammatory molecules, and upregulated IL-10 gene and protein expression. Guarana plus LLLT also decreased the levels of caspases 1, 3, and 8, increased the percentage of S-phase cells, and decreased FGF-1 and KGF-1 levels. Some of these changes were also observed after treatment with guarana or LLLT alone. CONCLUSIONS: Our results suggest that concomitant treatment with guarana and LLLT may promote fibroblast biostimulation and thus is clinically relevant.

Lentinan inhibits oxidative stress and inflammatory cytokine production induced by benzo(a)pyrene in human keratinocytes.

BACKGROUND: Benzo(a)pyrene, a major environmental pollutant, is known to accelerate skin aging through oxidative stress, increase the production of inflammatory mediators, and cause skin cancer. Lentinan, prepared from Lentinus edodes (Shiitake mushroom), has been reported to exhibit anti-coagulant, anti-viral, anti-cancer, anti-tumor, and anti-coagulant effects. However, the effect of lentinan on human keratinocytes treated with benzo(a)pyrene is unknown. AIMS: The aim of this study was to explore whether lentinan inhibits benzo(a)pyrene-induced oxidative stress and inflammatory cytokine production in human keratinocytes. METHODS: We investigated the effect of lentinan on benzo(a)pyrene-induced oxidative stress indicators (malondialdehyde, superoxide dismutase, and glutathione peroxidase) in human immortalized keratinocytes (HaCaT cells). We also assessed the production of inflammatory factors interleukin-8 and chemokine ligand-2 induced by benzo(a)pyrene exposure at both mRNA and protein levels. RESULTS: Lentinan inhibited oxidative stress induced by benzo(a)pyrene, as shown by the concentration-dependent reduction in reactive oxygen species in HaCaT cells. In addition, malondialdehyde levels were reduced to 53% of those of cells treated with benzo(a)pyrene without lentinan. The activities of superoxide dismutase and glutathione peroxidase were approximately 18- and 2.7-fold higher in benzo(a)pyrene-treated cells with lentinan than in those without lentinan. Moreover, lentinan significantly reduced interleukin-8 and chemokine ligand-2 mRNA and protein levels. CONCLUSIONS: These findings suggest that lentinan has two biological activities that are potentially useful for managing inflammatory skin diseases or disorders related to oxidative stress induced by benzo(a)pyrene. Therefore, cosmetics containing L edodes have promising dermatological applications, with potential utility in protecting the skin against environmental pollutants.

Protective Effects of Kuding Tea (Ilex kudingcha C. J. Tseng) Polyphenols on UVB-Induced Skin Aging in SKH1 Hairless Mice.

In this study, the protective effects of Kuding tea polyphenols (KTPs) on ultraviolet B (UVB)-induced skin injury of SKH1 hairless mice were studied. The ion precipitation method was used for extraction of polyphenols from Kuding tea. High-performance liquid chromatography showed that KTPs contains chlorogenic acid, cryptochlorogenic acid, isochlorogenic acid B, isochlorogenic acid A, and isochlorogenic acid C. SKH1 hairless mice were induced skin aging using 2.0 mW/s intensity of 90 mJ/cm² UV light once a day for seven weeks. The 2.5% and 5% KTPs solution was smeared on 2 cm² of back skin of skin aging mice twice a day. Mouse experiments showed that KTP strongly increased the serum levels of total superoxide dismutase (T-SOD) and catalase (CAT) and reduced those of malondialdehyde, interleukin 6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNF-α) in mice with UVB-induced skin damage. KTP also increased the levels of type 1 collagen (Col I), hydroxyproline, and hyaluronic acid and reduced those of Col III and hydrogen peroxide in the damaged skin tissues of mice. Pathological observations of tissues stained with H & E, Masson's trichrome, Verhoeff, and toluidine blue showed that KTPs could protect skin cells, collagen, and elastin and decrease the number of mast cells, thus inhibiting skin damage. Quantitative PCR and western blot assays showed that KTP upregulated the mRNA and protein expression of tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, copper/zinc-SOD, manganese-SOD, CAT, and glutathione peroxidase and downregulated the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. In addition, the same concentration of KTP had stronger protective effects than vitamin C. The results of this study demonstrate that KTPs have good skin protective effects, as they are able to inhibit UVB-induced skin damage.

Aged human skin accumulates mast cells with altered functionality that localize to macrophages and vasoactive intestinal peptide-positive nerve fibres.

BACKGROUND: Skin health declines with age and this is partially attributed to immunosenescence. Mast cells (MCs) are innate immune cells that coordinate tissue immune responses integral to skin homeostasis and disease. OBJECTIVES: To understand how MCs contribute to human skin ageing, we investigated how intrinsic ageing impacts MC phenotype and MC relationships with other immune cells and skin structures. METHODS: In photoprotected skin biopsies from young (≤ 30 years) and aged (≥ 75 years) individuals, immunostaining and spatial morphometry were performed to identify changes in MC phenotype, number, distribution and interaction with the vasculature and nerve fibres. Quantitative polymerase chain reaction was used to measure changes in gene expression related to immune cell activity and neuropeptide signalling. RESULTS: Skin MCs, macrophages and CD8+ T cells increased in number in intrinsically aged vs. young skin by 40%, 44% and 90%, respectively (P < 0·05), while CD4+ T cells and neutrophils were unchanged. In aged skin, MCs were more numerous in the papillary dermis and showed a reduced incidence of degranulation (50% lower than in young, P < 0·01), a conserved tryptase-chymase phenotype and coexpression of granzyme B. In aged skin, MCs increased their association with macrophages (~ 48% vs. ~27%, P < 0·05) and nerve fibres (~29% vs. 16%, P < 0·001), while reducing their interactions with blood vessels (~34% vs. 45%, P < 0·001). Additionally, we observed modulation of gene expression of vasoactive intestinal peptide (VIP; increased) and substance P (decreased) with age; this was associated with an increased frequency of VIP+ nerve fibres (around three times higher in aged skin, P < 0·05), which were strongly associated with MCs (~19% in aged vs. 8% in young, P < 0·05). CONCLUSIONS: In photoprotected skin we observed an accumulation of MCs with increasing age. These MCs have both altered functionality and distribution within the skin, which supports a role for these cells in altered tissue homeostasis during ageing.

The Essential Role of Ca2+ Signals in UVB-Induced IL-1ß Secretion in Keratinocytes.

UVB-induced skin damage is attributable to reactive oxygen species, which are triggered by intracellular Ca2+ signals. However, exactly how the reactive oxygen species are triggered by intracellular Ca2+ upon UVB irradiation remains obscure. Here, we show that UVB induces Ca2+ signals via sequential generation of the following Ca2+ messengers: inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate, and cyclic ADP-ribose. UVB induced H2O2 production through NADPH oxidase 4 activation, which is downstream to inositol 1,4,5-trisphosphate and nicotinic acid adenine dinucleotide phosphate. H2O2 derived from NADPH oxidase 4 activated CD38 to produce cyclic ADP-ribose. UVB first evoked the pannexin channel to release ATP, which acts on P2X7 receptor to generate inositol 1,4,5-trisphosphate. Inhibitors of these messengers, as well as antioxidants, blocked UVB-induced Ca2+ signals and IL-1ß secretion in keratinocytes. Furthermore, ablation of CD38 and NADPH oxidase 4 protected against UVB-induced inflammation and IL-1ß secretion in the murine epidermis. These results show that UVB induces IL-1ß secretion through cross-talk between Ca2+ and reactive oxygen species, providing insight towards potential targets against UVB-induced inflammation.

Clove attenuates UVB-induced photodamage and repairs skin barrier function in hairless mice.

Syzygium aromaticum L., commonly named clove, is widely used in the food industry due to its antioxidant and antibacterial capabilities. However, little information is available regarding its role in resisting skin photoaging. This study investigated 50% ethanol extract of Syzygium aromaticum L. (SA) and eugenol (EO) for anti-aging effects in UVB-irradiated normal human dermal fibroblasts (NHDFs) and hairless mice. In vitro, SA and EO suppressed matrix metalloproteinase-1, 3 (MMP-1 and MMP-3) secretion as well as the activator protein 1 (AP-1) phosphorylation. SA and EO also activated nuclear erythroid 2-related factor/antioxidant-response element (Nrf2/ARE) signaling which improves the antioxidant activity and inhibited nuclear factor-κB (NF-κB) and interleukin-6 (IL-6) expression, pro-inflammatory factors. Furthermore, SA and EO suppressed the nuclear factor of activated T cells c1 (NFATc1) which is a known activator of MMPs, cooperator transforming growth factor beta (TGF-ß) and NF-κB in Ca2+/calcineurin-regulated transcription. In vivo, SA significantly improved the levels of procollagen type I and elastin through TGF/Smad signaling. The histopathological studies found that SA reduced wrinkles. SA also increased filament aggregating protein (filaggrin), which repairs the skin barrier function and improved the skin's hydration. Altogether, SA effectively ameliorated UVB-induced photoaging. It is expected to become a promising natural product.

Chronic immunosuppression in the mature patient.

In the ever-aging population of the world, the field of geriatrics continues to grow in importance. As human beings age, the skin undergoes a unique array of changes that predispose it to a specific set of dermatoses, infections, and neoplasms. Some of these physiologic alterations are comparable to the changes that happen in immunosuppressed individuals. Given the importance of immunosuppressive medications in treatment of many common skin conditions, we have reviewed the current literature to assist the practicing clinician in using immunosuppressive medications in the geriatric population.

Imbalance of Mitochondrial Respiratory Chain Complexes in the Epidermis Induces Severe Skin Inflammation.

Accumulation of large-scale mitochondrial DNA (mtDNA) deletions and chronic, subclinical inflammation are concomitant during skin aging, thus raising the question of a causal link. To approach this, we generated mice expressing a mutant mitochondrial helicase (K320E-TWINKLE) in the epidermis to accelerate the accumulation of mtDNA deletions in this skin compartment. Mice displayed low amounts of large-scale deletions and a dramatic depletion of mtDNA in the epidermis and showed macroscopic signs of severe skin inflammation. The mtDNA alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression, causing a severe inflammatory phenotype, with massive immune cell infiltrates already before birth. Altogether, these data unraveled a previously unknown link between an imbalanced stoichiometry of the mitochondrial respiratory chain complexes and skin inflammation and suggest that severe respiratory chain dysfunction, as observed in few cells leading to a mosaic in aged tissues, might be involved in the development of chronic subclinical inflammation.

Hyaluronan: More than just a wrinkle filler.

Dermatology is a field that strives not only to alleviate skin disease (therapeutics) but also to improve the perception of wellness (cosmetics). Thus, in this special issue of Glycobiology, it seems appropriate to discuss the biology of a glycosaminoglycan, called hyaluronic acid (hyaluronan, or HA), that has become the most popular agent today for intradermal injections to improve wrinkles and other cosmetic defects. HA is a simple linear polymer in which a simple disaccharide is repeated thousands of time, thereby creating a huge hydrophilic molecule that confers a large volume of hydration and contributes to the turgor and flexibility of healthy skin. Beyond cosmetic considerations, however, HA also has important biological and physiological functions that were largely under-appreciated until recently. New research has confirmed that HA is dynamically produced by most skin cells, not only fibroblasts (the cells that make most of the skin's extracellular matrix) but also by keratinocytes in the outer protective layer (epidermis). For both fibroblasts and keratinocytes, HA plays a regulatory role in controlling cell physiology through interaction of extracellular HA with a major cell-surface receptor, CD44. This interaction mediates intracellular signaling both directly and indirectly, through CD44 interactions with the cytoskeleton and with EGF and TGFß receptors. Furthermore, degradation of HA by specific hyaluronidase enzymes produces HA fragments that can help to regulate inflammatory processes. In this review, current knowledge about the role of HA in skin inflammation and wound healing are reviewed and possible future applications of such knowledge discussed.