[TGF-ß : A key player in age-related loss of skin innate immunity]. / TGF-ß : un acteur essentiel de la perte d'immunité innée du tissu cutané au cours du vieillissement - L'actualité scientifique vue par les étudiants du Master Biologie Santé, module physiopathologie de la signalisation, Université Paris-Saclay.

TITLE: TGF-ß : un acteur essentiel de la perte d'immunité innée du tissu cutané au cours du vieillissement - L'actualité scientifique vue par les étudiants du Master Biologie Santé, module physiopathologie de la signalisation, Université Paris-Saclay. ABSTRACT: Pour la sixième année, dans le cadre du module d'enseignement « Physiopathologie de la signalisation ¼ proposé par l'université Paris-sud, les étudiants du Master « Biologie Santé ¼ de l'université Paris-Saclay se sont confrontés à l'écriture scientifique. Ils ont sélectionné une quinzaine d'articles scientifiques récents dans le domaine de la signalisation cellulaire présentant des résultats originaux, via des approches expérimentales variées, sur des thèmes allant des relations hôte-pathogène aux innovations thérapeutiques, en passant par la signalisation hépatique et le métabolisme. Après un travail préparatoire réalisé avec l'équipe pédagogique, les étudiants, organisés en binômes, ont ensuite rédigé, guidés par des chercheurs, une Nouvelle soulignant les résultats majeurs et l'originalité de l'article étudié. Ils ont beaucoup apprécié cette initiation à l'écriture d'articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme ! Trois de ces Nouvelles sont publiées dans ce numéro, les autres le seront dans des prochains numéros.

The Return of the Mast Cell: New Roles in Neuroimmune Itch Biology.

The mast cell-nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell-nerve unit in itch biology.

Antimicrobial peptides activity in the skin.

This review presents the current state of knowledge regarding multifunctional role of human skin antimicrobial peptides (AMPs), including (a) protection from microbial infection, (b) improvement of skin barrier homoeostasis, (c) modulation of inflammation responses, and (d) promotion of wound healing. In addition, association of AMPs with skin diseases as well as challenges and future prospects for AMP therapeutics has also been discussed.

Time to Abandon Antimicrobial Approaches in Wound Healing: A Paradigm Shift.

Antimicrobial approaches (eg, antibiotics and antiseptics) have been used for decades in the treatment of infected wounds, ulcers, and burns. However, an increasing number of meta-analyses have raised questions regarding the therapeutic value of these approaches. Newer findings show that the body actively hosts an ecosystem of bacteria, fungi, viruses, and mites on its outer surfaces, known as the microbiome, as part of its defense against pathogens. Antimicrobials would disrupt this system and thereby work against the strategy the body has chosen. Recently, a new technology, micropore particle technology (MPPT), has been identified; it is not an antimicrobial but instead acts as a passive immunotherapy that disrupts the weaponry bacteria and fungi use to inhibit the immune system, allowing the immune system to recover. Clinical findings show MPPT removes wound infections 60% quicker than antibiotics and antiseptics and promotes the healing of chronic wounds that have not responded to antimicrobials. These effects are achieved without antimicrobial action and, considering the limited therapeutic benefits of antibiotics and antiseptics for wound infections, it is valid to question the use of antimicrobial approaches in wound care and the dogma that a reduction in microbial burden will lead to a reduction in infection. Instead, it may be time to consider a paradigm shift in wound healing away from antimicrobials and towards therapies that support the immune system and the microbiome. This review covers the increasing evidence that infections on external surfaces have to be treated fundamentally differently to internal infections.

Type III Interferons in Antiviral Defenses at Barrier Surfaces.

Barrier surfaces such as the epithelium lining the respiratory and gastrointestinal (GI) tracts, the endothelium comprising the blood-brain barrier (BBB), and placental trophoblasts provide key physical and immunological protection against viruses. These barriers utilize nonredundant mechanisms to suppress viral infections including the production of interferons (IFNs), which induce a strong antiviral state following receptor binding. However, whereas type I IFNs control infection systemically, type III IFNs (IFN-λs) control infection locally at barrier surfaces and are often preferentially induced by these cells. In this review we focus on the role of IFN-λ at barrier surfaces, focusing on the respiratory and GI tracts, the BBB, and the placenta, and on how these IFNs act to suppress viral infections.

Peripheral Tissue Chemokines: Homeostatic Control of Immune Surveillance T Cells.

Cellular immunity is governed by a complex network of migratory cues that enable appropriate immune cell responses in a timely and spatially controlled fashion. This review focuses on the chemokines and their receptors regulating the steady-state localisation of immune cells within healthy peripheral tissues. Steady-state immune cell traffic is not well understood but is thought to involve constitutive (homeostatic) chemokines. The recent discovery of tissue-resident memory T cells (TRM cells) illustrates our need for understanding how chemokines control immune cell mobilisation and/or retention. These studies will be critical to unravel novel pathways for preserving tissue function (aging) and preventing tissue disease (vaccination).

[Neuroimmune interactions in the skin: a link between pain and immunity]. / Interactions neuro-immunes dans la peau - Un lien entre douleur et immunité.

Upon infection, our ability to eliminate pathogens depends mostly on our immune system. However, recent studies have shown that the nervous system plays a role in controlling infectious and inflammatory processes. Bidirectional functional interactions are established between the nervous and immune systems to protect tissue integrity. The skin is one of the first lines of defense against external threats and has a particularly well-developed neuroimmune system. Challenges to the skin activate neurons specialized in pain perception, which regulate immune cell functions and recruitment to tissues. We illustrate the importance of such neuroimmune regulation here, through the example of several skin diseases.

Smart Garment Fabrics to Enable Non-Contact Opto-Physiological Monitoring.

Imaging photoplethysmography (iPPG) is an emerging technology used to assess microcirculation and cardiovascular signs by collecting backscattered light from illuminated tissue using optical imaging sensors. The aim of this study was to study how effective smart garment fabrics could be capturing physiological signs in a non-contact mode. The present work demonstrates a feasible approach of, instead of using conventional high-power illumination sources, integrating a grid of surface-mounted light emitting diodes (LEDs) into cotton fabric to spotlight the region of interest (ROI). The green and the red LEDs (525 and 660 nm) placed on a small cotton substrate were used to locally illuminate palm skin in a dual-wavelength iPPG setup, where the backscattered light is transmitted to a remote image sensor through the garment fabric. The results show that the illuminations from both wavelength LEDs can be used to extract heart rate (HR) reaching an accuracy of 90% compared to a contact PPG probe. Stretching the fabric over the skin surface alters the morphology of iPPG signals, demonstrating a significantly higher pulsatile amplitude in both channels of green and red illuminations. The skin compression by the fabric could be potentially utilised to enhance the penetration of illumination into cutaneous microvascular beds. The outcome could lead a new avenue of non-contact opto-physiological monitoring and assessment with functional garment fabrics.

Delivery of monocyte lineage cells in a biomimetic scaffold enhances tissue repair.

The monocyte lineage is essential to normal wound healing. Macrophage inhibition or knockout in mice results in impaired wound healing through reduced neovascularization, granulation tissue formation, and reepithelialization. Numerous studies have either depleted macrophages or reduced their activity in the context of wound healing. Here, we demonstrate that by increasing the number of macrophages or monocytes in the wound site above physiologic levels via pullulan-collagen composite dermal hydrogel scaffold delivery, the rate of wound healing can be significantly accelerated in both wild-type and diabetic mice, with no adverse effect on the quality of repair. Macrophages transplanted onto wounds differentiate into M1 and M2 phenotypes of different proportions at various time points, ultimately increasing angiogenesis. Given that monocytes can be readily isolated from peripheral blood without in vitro manipulation, these findings hold promise for translational medicine aimed at accelerating wound healing across a broad spectrum of diseases.

Human reconstructed skin xenografts on mice to model skin physiology.

Xenograft models to study skin physiology have been popular for scientific use since the 1970s, with various developments and improvements to the techniques over the decades. Xenograft models are particularly useful and sought after due to the lack of clinically relevant animal models in predicting drug effectiveness in humans. Such predictions could in turn boost the process of drug discovery, since novel drug compounds have an estimated 8% chance of FDA approval despite years of rigorous preclinical testing and evaluation, albeit mostly in non-human models. In the case of skin research, the mouse persists as the most popular animal model of choice, despite its well-known anatomical differences with human skin. Differences in skin biology are especially evident when trying to dissect more complex skin conditions, such as psoriasis and eczema, where interactions between the immune system, epidermis and the environment likely occur. While the use of animal models are still considered the gold standard for systemic toxicity studies under controlled environments, there are now alternative models that have been approved for certain applications. To overcome the biological limitations of the mouse model, research efforts have also focused on "humanizing" the mice model to better recapitulate human skin physiology. In this review, we outline the different approaches undertaken thus far to study skin biology using human tissue xenografts in mice and the technical challenges involved. We also describe more recent developments to generate humanized multi-tissue compartment mice that carry both a functioning human immune system and skin xenografts. Such composite animal models provide promising opportunities to study drugs, disease and differentiation with greater clinical relevance.

Skin innate immune response to flaviviral infection.

Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika and West Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.

The antimicrobial peptide derived from insulin-like growth factor-binding protein 5, AMP-IBP5, regulates keratinocyte functions through Mas-related gene X receptors.

BACKGROUND: In addition to their microbicidal properties, host defense peptides (HDPs) display various immunomodulatory functions, including keratinocyte production of cytokines/chemokines, proliferation, migration and wound healing. Recently, a novel HDP named AMP-IBP5 (antimicrobial peptide derived from insulin-like growth factor-binding protein 5) was shown to exhibit antimicrobial activity against numerous pathogens, even at concentrations comparable to those of human ß-defensins and LL-37. However, the immunomodulatory role of AMP-IBP5 in cutaneous tissue remains unknown. OBJECTIVES: To investigate whether AMP-IBP5 triggers keratinocyte activation and to clarify its mechanism. METHODS: Production of cytokines/chemokines and growth factors was determined by appropriate ELISA kits. Cell migration was assessed by in vitro wound closure assay, whereas cell proliferation was analyzed using BrdU incorporation assay complimented with XTT assay. MAPK and NF-κB activation was determined by Western blotting. Intracellular cAMP levels were assessed using cAMP enzyme immunoassay kit. RESULTS: Among various cytokines/chemokines and growth factors tested, AMP-IBP5 selectively increased the production of IL-8 and VEGF. Moreover, AMP-IBP5 markedly enhanced keratinocyte migration and proliferation. AMP-IBP5-induced keratinocyte activation was mediated by Mrg X1-X4 receptors with MAPK and NF-κB pathways working downstream, as evidenced by the inhibitory effects of MrgX1-X4 siRNAs and ERK-, JNK-, p38- and NF-κB-specific inhibitors. We confirmed that AMP-IBP5 indeed induced MAPK and NF-κB activation. Furthermore, AMP-IBP5-induced VEGF but not IL-8 production correlated with an increase in intracellular cAMP. CONCLUSIONS: Our findings suggest that in addition to its antimicrobial function, AMP-IBP5 might contribute to wound healing process through activation of keratinocytes.

Antimicrobial Peptides, Infections and the Skin Barrier.

The skin serves as a strong barrier protecting us from invading pathogens and harmful organisms. An important part of this barrier comes from antimicrobial peptides (AMPs), which are small peptides expressed abundantly in the skin. AMPs are produced in the deeper layers of the epidermis and transported to the stratum corneum, where they play a vital role in the first line of defense against potential pathogens. Numerous AMPs exist, and they have a broad antibiotic-like activity against bacteria, fungi and viruses. They also act as multifunctional effector molecules, linking innate and adaptive immune responses. AMPs play an essential part in maintaining an optimal and functional skin barrier - not only by direct killing of pathogens, but also by balancing immune responses and interfering in wound healing, cell differentiation, reepithelialization and their synergistic interplay with the skin microflora.

Skin Barrier Function and Allergens.

The skin is an important barrier protecting us from mechanical insults, microorganisms, chemicals and allergens, but, importantly, also reducing water loss. A common hallmark for many dermatoses is a compromised skin barrier function, and one could suspect an elevated risk of contact sensitization (CS) and allergy following increased penetration of potential allergens. However, the relationship between common dermatoses such as psoriasis, atopic dermatitis (AD) and irritant contact dermatitis (ICD) and the development of contact allergy (CA) is complex, and depends on immunologic responses and skin barrier status. Psoriasis has traditionally been regarded a Th1-dominated disease, but the discovery of Th17 cells and IL-17 provides new and interesting information regarding the pathogenesis of the disease. Research suggests an inverse relationship between psoriasis and CA, possibly due to increased levels of Th17 cells and its associated cytokines. As for AD, a positive association to CS has been established in epidemiological studies, but is still unresolved. Experimental studies show, however, an inverse relationship between AD and CS. The opposing and antagonistic influences of Th1 (CS) and Th2 (AD) have been proposed as an explanation. Finally, there is convincing evidence that exposure to irritants increases the risk of CS, and patients with ICD are, therefore, at great risk of developing CA. Skin irritation leads to the release of IL-1 and TNF-α, which affects the function of antigen-presenting cells and promotes their migration to local lymph nodes, thus increasing the probability of CS and ultimately the development of CA.

NFLUENCE OF MAST CELLS ON REPARATIVE REGENERATION OF TISSUES WITH DIFFERENT DEGREE OF IMMUNOLOGICAL PRIVILEGES.

It is assumed that tissues with different degree of imminological privileges have a number of distinctions in the processes of reparation. This may be associated with mast cells, which are found in all body tissues of an organism, secrete a wide range of biologically active substances and are important in the regulation of repair processes. This paper present the results of investigations of morphometric parameners and functional activity of mast cells in tissues with varying degrees of immune privilege (skin, testis). It has been shown that migration of must cells in the skin is observed early after the injury and followed by a slow increase of synthetic activity and index of degranulation of mastocytes within 30 days. Index of degranulation of mast cells in the testes increased immediately after the injury in the absence of their pronounced migration. Stabilizing membranes of mast cells using the drug ketotifen led to inhibition of the repair of the skin, which was manifested itself in the absence of increasing the thickness of dermis, epidermis, the number of fibroblasts and collagen fibers, and also in slowing down the formation of scar. At the same time, the inactivation of mast cells promoted reparative regeneration of testes as was indicated by increase in the number of normal spermatogonia which are proliferative pool for all subsequent stages of spermatogenesis, and by considerable decrease in the number of non-functioning tubules. Thus, the number and the functional sate of the mast cells have an impact on the course of reparative processes in tissues with varying degrees of immune privileges.

Highly abundant defense proteins in human sweat as revealed by targeted proteomics and label-free quantification mass spectrometry.

BACKGROUND: The healthy human skin with its effective antimicrobial defense system forms an efficient barrier against invading pathogens. There is evidence suggesting that the composition of this chemical barrier varies between diseases, making the easily collected sweat an ideal candidate for biomarker discoveries. OBJECTIVE: Our aim was to provide information about the normal composition of the sweat, and to study the chemical barrier found at the surface of skin. METHODS: Sweat samples from healthy individuals were collected during sauna bathing, and the global protein panel was analysed by label-free mass spectrometry. SRM-based targeted proteomic methods were designed and stable isotope labelled reference peptides were used for method validation. RESULTS: Ninety-five sweat proteins were identified, 20 of them were novel proteins. It was shown that dermcidin is the most abundant sweat protein, and along with apolipoprotein D, clusterin, prolactin-inducible protein and serum albumin, they make up 91% of secreted sweat proteins. The roles of these highly abundant proteins were reviewed; all of which have protective functions, highlighting the importance of sweat glands in composing the first line of innate immune defense system, and maintaining the epidermal barrier integrity. CONCLUSION: Our findings with regard to the proteins forming the chemical barrier of the skin as determined by label-free quantification and targeted proteomics methods are in accordance with previous studies, and can be further used as a starting point for non-invasive sweat biomarker research.