Clinical and metagenomic profiling of hormonal acne-prone skin in different populations.

INTRODUCTION: Acne is one of the most common skin concerns of unknown etiology, often connected to the menstrual cycle in women, and possibly to the microbial profile and function. OBJECTIVE: We aimed to investigate how hormonal fluctuation affects hormonal acne-prone skin in different populations in relation to skin clinical parameters and microbial profiles. METHODS: We evaluated skin features by using biophysical and topographical tools. For microbial profiling, we sequenced facial skin microbiota and associated the findings with the skin clinical parameters during the different phases of the menstrual cycle. RESULTS: We identified differences between and within hormonal phases in women of Chinese and Caucasian origin. Changes were discovered in transepidermal water loss (TEWL), sebum level, hydration level, and pore volume. The most abundant identifiable genera in both ethnicities were Cutibacterium, Staphylococcus, and Streptococcus, without any significant abundant differences within the menstrual cycle. Interestingly, 11 bacterial metabolic pathways were downregulated in Chinese compared to Caucasian skin during the follicular phase. The majority of these pathways were associated with skin redox balance, perhaps indicating a weaker oxidative stress response in Chinese versus Caucasian skin. Novosphingobium taxa were increased in the Chinese skin microbiome, which has been reported to protect skin from pollution-mediated oxidative stress. CONCLUSION: Thus, this pilot study explored some of the clinical and metagenomic changes in acne-prone skin, and provide guidance to tailor-personalized skin care regimes during the menstrual cycle. Also, the skin redox status in acne-prone skin, provides more opportunity to tailor-personalized skin care regimes.

Targeting microRNA for improved skin health.

BACKGROUND: In human skin, miRNAs have important regulatory roles and are involved in the development, morphogenesis, and maintenance by influencing cell proliferation, differentiation, immune regulation, and wound healing. MiRNAs have been investigated for many years in various skin disorders such as atopic dermatitis, psoriasis, as well as malignant tumors. Only during recent times, cosmeceutical use of molecules/natural active ingredients to regulate miRNA expression for significant advances in skin health/care product development was recognized. AIM: To review miRNAs with the potential to maintain and boost skin health and avoid premature aging by improving barrier function, preventing photoaging, hyperpigmentation, and chronological aging/senescence. METHODS: Most of the cited articles were found through literature search on PubMed. The main search criteria was a keyword "skin" in combination with the following words: miRNA, photoaging, UV, barrier, aging, exposome, acne, wound healing, pigmentation, pollution, and senescence. Most of the articles reviewed for relevancy were published during the past 10 years. RESULTS: All results are summarized in Figure 1, and they are based on cited references. CONCLUSIONS: Thus, regulating miRNAs expression is a promising approach for novel therapy not only for targeting skin diseases but also for cosmeceutical interventions aiming to boost skin health.

The Skin Interactome: A Holistic "Genome-Microbiome-Exposome" Approach to Understand and Modulate Skin Health and Aging.

Higher demands on skin care cosmetic products for strong performance drive intense research to understand the mechanisms of skin aging and design strategies to improve overall skin health. Today we know that our needs and influencers of skin health and skin aging change throughout our life journey due to both extrinsic factors, such as environmental factors and lifestyle factors, as well as our intrinsic factors. Furthermore, we need to consider our microflora, a collection of micro-organisms such as bacteria, viruses, and fungi, which is a living ecosystem in our gut and on our skin, that can have a major impact on our health. Here, we are viewing a holistic approach to understand the collective effect of the key influencers of skin health and skin aging both reviewing how each of them impact the skin, but more importantly to identify molecular conjunction pathways of these different factors in order to get a better understanding of the integrated "genome-microbiome-exposome" effect. For this purpose and in order to translate molecularly the impact of the key influencers of skin health and skin aging, we built a digital model based on system biology using different bioinformatics tools. This model is considering both the positive and negative impact of our genome (genes, age/gender), exposome: external (sun, pollution, climate) and lifestyle factors (sleep, stress, exercise, nutrition, skin care routine), as well as the role of our skin microbiome, and allowed us in a first application to evaluate the effect of the genome in the synthesis of collagen in the skin and the determination of a suitable target for boosting pro-collagen synthesis. In conclusion, we have, through our digital holistic approach, defined the skin interactome concept, as an advanced tool to better understand the molecular genesis of skin aging and further develop a strategy to balance the influence of the exposome and microbiome to protect, prevent, and delay the appearance of skin aging signs and preserve good skin health condition. In addition, this model will aid in identifying and optimizing skin treatment options based on external triggers, as well as helping to design optimal treatments modulating the intrinsic pathways.

A novel multifunctional skin care formulation with a unique blend of antipollution, brightening and antiaging active complexes.

BACKGROUND: High demand on anti-aging skin care encourage the improvement and development of more personalized formulations with additional benefits for general skin health and age associated skin signs. The skin aging physical and biological phenotypes manifest differently between diverse ethnic populations. A highly polluted environment can be viewed as an extrinsic factor accelerating the skin aging process. AIM: To develop a unique formula with active complexes, having multifunctional effects for anti-pollution, brightening and anti-aging/barrier strengthening purposes with confirmed activities in vitro and ex vivo skin models, suitable for polluted skin. METHODS: In vitro culture model with primary human skin cells, ex vivo studies with full-thickness human skin, melanocyte 3D coculture model, gene expression of epidermal and dermal genes, anti-glycation, proteasomal activity, melanin, and cytokine assays. RESULTS: In vitro and ex vivo studies clearly demonstrated that diglucosyl gallic acid (active A) and the formulation complex inhibited pollution mediated MMP1 protein, CYP1A1 gene expression, and IL-6 protein secretion, while caprylic/capric triglyceride, diacetyl boldine (active B) had anti-melanogenic effect in in vitro primary melanocyte monoculture and 3D spheroid model. Another active compound, acetyl dipeptide 1 cetyl ester (active D), significantly upregulated epidermal barrier genes (Aquaporin 3 [AQP3], Filaggrin [FLG], caspase 14, and keratin 10) in human primary keratinocytes. Interestingly, both acetyl dipeptide 1 cetyl ester (active D) and niacinamide (active C) improved dermal gene expression (fibrillin-1, Collagen type 1 alpha 1, Decorin, Lysyl oxidase-like 1) and, moreover, had significant anti-glycant and proteasomal promoter activity in human primary fibroblasts. CONCLUSION: Considering consumers need in heavily polluted areas, we developed a multipurpose formulation comprised of unique active complexes toward pollution, pollution induced inflammation, skin brightening, and antiaging concerns with beneficial results demonstrated by in vitro and ex vivo studies.

Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons.

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

Lactobacillus reuteri DSM 17938-A comparative study on the effect of probiotics and lysates on human skin.

Human skin microbiota might play an important role in maintaining skin health and potentially prevent premature skin ageing. The use of probiotics in therapeutic skin applications is an attractive idea, as it could offer an alternative option for certain inflammatory skin disorders and dry or sensitive skin. Here, we investigated for the first time, a comparative study of live and the lysate products of probiotic strain Lactobacillus reuteri DSM 17938 in skin topical applications using ex vivo skin models focusing on anti-inflammatory and skin barrier function and in vitro assays for antimicrobial activity. Our results in ultraviolet B radiation (UVB-R)-induced inflammation model demonstrated that both live bacteria and the lysate of L. reuteri DSM 17938 reduced proinflammatory IL-6 and IL-8, illustrated in both reconstructed human epidermis (RHE) and native skin models. Live L reuteri DSM 17938 significantly increased aquaporin 3 (AQP3) gene expression, while the lysate enhanced laminin A/B levels in a healthy (unstimulated) state of RHE, suggesting a positive impact on skin barrier. In addition, live L. reuteri DSM 17938 had antimicrobial action against pathogenic skin bacteria (Staphylococcus aureus, Streptococcus pyogenes M1, Cutibacterium acnes AS12, Pseudomonas aeruginosa), whereas the lysate did not have such an effect. Therefore, it is hypothesized that L. reuteri DSM 17938 could be beneficial for general skin health, to avoid the UVB-R-mediated inflammatory cascade and/or prevent photoageing, improve barrier function or in the management of unhealthy skin prone to inflammatory conditions due to its antimicrobial, anti-inflammatory and skin barrier enhancing functions.

B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production.

Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.

Reactive oxygen species in psoriasis and psoriasis arthritis: relevance to human disease.

Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development.

Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice.

Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by γδ T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcγ receptor III, mast cells, and histamine) and adaptive immune players (αß T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-α secretion and stimulation of local γδ T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.

Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen II.

We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.