Search

The cutaneous microbiota comprises all living skin microorganisms. There is increasing evidence that the microbiota plays a crucial role in skin homeostasis. Accordingly, a dysbiosis of the microbiota may trigger cutaneous inflammation. The need for a balanced microbiota requires specific regulatory mechanisms that control and shape the microbiota. In this review, we highlight the present knowledge suggesting that antimicrobial peptides (AMPs) may exert a substantial influence on the microbiota by controlling their growth. This is supported by own data showing the differential influence of principal skin-derived AMPs on commensal staphylococci. Vice versa, we also illuminate how the cutaneous microbiota interacts with skin-derived AMPs by modulating AMP expression and how microbiota members protect themselves from the antimicrobial activity of AMPs. Taken together, the current picture suggests that a fine-tuned and well-balanced AMP-microbiota interplay on the skin surface may be crucial for skin health., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

In the May issue of Experimental Dermatology 2018, we published a review article focusing on human 3D skin models in the context of microbiota research. The principal intention was to provide an overview of present and future concepts to use skin models in microbiota analyses. With the present viewpoint, we would like to draw the reader's attention again to the use of human skin models in microbiota research with the aim to highlight the benefits and necessity of human skin models to analyse the human skin-microbiota interaction. This is accompanied by a critical view on mice models that often are not suitable to analyse the functional impact of the human skin microbiota. In addition, we present novel and future concepts highlighting the benefits of human 3D skin models in microbiota research., (© 2020 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

The human ribonuclease RNase 7 has been originally isolated from human skin and is a member of the human RNase A superfamily. RNase 7 is constantly released by keratinocytes and accumulates on the skin surface. The expression of RNase 7 in keratinocytes can be induced by diverse stimuli such as cytokines, growth factors, and microbial factors. RNase 7 exhibits a potent broad spectrum of antimicrobial activity against various microorganisms and contributes to control bacterial growth on the skin surface. The ribonuclease and antimicrobial activity of RNase 7 can be blocked by the endogenous ribonuclease inhibitor. There is also increasing evidence that RNase 7 exerts immunomodulatory activities and may participate in antiviral defense. In this review, we discuss how these characteristics of RNase 7 contribute to innate cutaneous defense and highlight its role in skin infection and inflammation. We also speculate how a potential dysregulation of RNase 7 promotes inflammatory skin diseases and if RNase 7 may have therapeutic potential., (Copyright © 2019 Rademacher, Dreyer, Kopfnagel, Gläser, Werfel and Harder.)

Staphylococcus epidermidis is an abundant skin commensal capable of activating cutaneous defense responses, such as induction of cytokines and antimicrobial peptides. To permanently colonize human skin and prevent inflammation S. epidermidis needs to control the induction of host defense mediators. We report here that S. epidermidis induces expression of the host regulator protein A20 in human keratinocytes, thereby controlling expression and release of interleukin-1 beta. siRNA-mediated knockdown of A20 expression strongly enhanced the induction of interleukin-1 beta gene expression and protein release in keratinocytes stimulated with S. epidermidis. Furthermore, siRNA-mediated knockdown of A20 resulted in enhanced gene expression and secretion of the antimicrobial peptide human beta-defensin-2 in keratinocytes facing S. epidermidis. Mechanistically, A20 negatively controlled S. epidermidis-induced activation of the transcription factor NF-kappaB. Together, these data indicate that S. epidermidis exploits A20 to attenuate cutaneous defense responses, which may help S. epidermidis to persist on human skin.

Bacterial challenge of keratinocytes with the abundant skin commensal Staphylococcus epidermidis induces distinct innate immune responses, but the underlying molecular mechanisms are still emerging. We report that the aryl hydrocarbon receptor (AhR) was activated in human primary keratinocytes infected with S. epidermidis, leading to induction of the AhR-responsive gene cytochrome P450 1A1 (CYP1A1). In addition, functional AhR was required for S. epidermidis-mediated induction of IL-1β expression in keratinocytes. AhR-dependent gene induction of IL-1β and CYP1A1 was mediated by factor(s) < 2 kDa secreted by S. epidermidis. Blockade of the AhR in a 3D organotypic skin equivalent infected with S. epidermidis attenuated the S. epidermidis-induced CYP1A1 and IL-1β expression. Moreover, S. epidermidis also induced expression of IL-1α and of the antimicrobial peptide human β-defensin-3 in an AhR-dependent manner in a 3D skin equivalent. An increased outgrowth of S. epidermidis on the surface of skin explants treated with a specific AhR inhibitor further indicate a pivotal role of the AhR in mediating an epidermal defense response. Taken together, our data expand the role of the AhR in innate immunity and support a previously unappreciated contribution for the AhR in cutaneous defense., (The Author(s). Published by S. Karger AG, Basel.)

Although the role of the microbiota in skin homeostasis is still emerging, there is growing evidence that an intact microbiota supports the skin barrier. The increasing number of research efforts that are trying to shed more light on the human skin-microbiota interaction requires the use of suitable experimental models. Three-dimensional (3D) skin equivalents have been established as a valuable tool in dermatological research because they contain a fully differentiated epidermal barrier that reflects the morphological and molecular characteristics of normal human epidermis. In this review, we provide an overview of current 3D skin models and illustrate the potential of 3D skin models to study the human skin-microbiota interplay., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Proteases and their inhibitors play an important role in epidermal homeostasis. Their imbalance contributes to severe skin diseases. SPINK7 is a member of the SPINK protease inhibitor family and has been described so far as a cancer-related gene in the esophagus. Herein, we describe for the first time its expression in healthy human skin. Moreover, SPINK7 is up-regulated in inflammatory skin diseases like psoriasis and eczema as demonstrated by immunohistochemistry, though real-time PCR analyses revealed no significant up-regulation. In cultured keratinocytes, SPINK7 mRNA expression was up-regulated by IL-17A together with IFNγ. Our observation points to a role of SPINK7 in skin homeostasis and its involvement in inflammatory skin diseases.

Nondiphtheria corynebacteria are typical members of the skin microbiota. However, in addition to being harmless inhabitants of healthy skin commensal skin-derived corynebacteria such as C. amycolatum occasionally also cause infections. This suggests that human skin must harbor adequate mechanisms to control the growth of corynebacteria on the skin surface. Here we show that keratinocytes are able to detect the presence of C. amycolatum leading to the epidermal growth factor receptor (EGFR)-dependent induction of the antimicrobial protein RNase 7. C. amycolatum-mediated induction of RNase 7 was also confirmed in a human 3D skin equivalent. The functional relevance of these findings was demonstrated by potent antimicrobial activity of RNase 7 against C. amycolatum and C. xerosis. In addition, the capacity of human stratum corneum to restrict the growth of C. amycolatum was significantly attenuated when RNase 7 was inactivated by a specific RNase 7-neutralizing antibody. Taken together, the interaction of RNase 7 with C. amycolatum indicates that RNase 7 may function as important effector molecule to control the growth of corynebacteria on human skin.

Millions of patients around the world suffer minor or major extremity amputation due to progressive wound healing complications of chronic or infected wounds, the therapy of which remains a challenge. One emerging therapeutic option for the treatment of these complicated wounds is the local application of an autologous thrombocytes concentrate lysate (e.g. platelet-released growth factors ((PRGF)) or Vivostat PRF ® ) that contains a multitude of chemokines, cytokines and growth factors and is therefore supposed to stimulate the complex wound healing process. Although PRGF and Vivostat PRF ® are already used successfully to support healing of chronic, hard-to-heal and infected wounds the underlying molecular mechanisms are not well understood. Psoriasin, also termed S100A7, is a multifunctional antimicrobial protein expressed in keratinocytes and is involved in various processes such as wound-healing, angiogenesis, innate immunity and immune-modulation. In this study, we investigated the influence of PRGF on psoriasin expression in human primary keratinocytes in vitro and the influence of Vivostat PRF ® on psoriasin expression in experimentally generated skin wounds in vivo. PRGF treatment of primary keratinocytes caused a significant concentration- and time-dependent increase of psoriasin gene and protein expression in vitro that were partially mediated by the epidermal growth factor receptor (EGFR) and the interleukin-6 receptor (IL-6R). In accordance with these cell culture data, Vivostat PRF ® induced a significant psoriasin gene and protein expression when applied to artificially generated skin wounds in vivo. The observed psoriasin induction in keratinocytes may contribute to the wound healing-promoting effects of therapeutically used thrombocyte concentrate lysates., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

The ribonuclease RNase 7 is a major skin-derived human antimicrobial protein expressed in keratinocytes. Here we show that the gram-negative pathogen Pseudomonas aeruginosa secretes factor(s) that induced RNase 7 gene and protein expression in human primary keratinocytes. The metalloprotease inhibitor marimastat, the epidermal growth factor receptor (EGFR) inhibitor AG1478 and the EGFR blocking antibody cetuximab significantly attenuated this induction, indicating an important role of the EGFR for the P. aeruginosa-mediated RNase 7 induction. In line with this, siRNA-mediated downregulation of ADAM17, a metalloprotease known to proteolytically mediate the release of soluble EGFR ligands, decreased the P. aeruginosa-mediated RNase 7 induction in keratinocytes. The impact of the EGFR was also demonstrated in a human 3D skin equivalent where blockade of the EGFR diminished induction of RNase 7 by P. aeruginosa. Blockade of Toll-like receptor 5 (TLR5), a pattern recognition receptor (PRR) known to be activated by P. aeruginosa, only moderately reduced the P. aeruginosa-mediated RNase 7 induction in keratinocytes. The functional relevance of RNase 7 to participate in cutaneous defense against P. aeruginosa was demonstrated by antibodies that neutralized the antimicrobial activity of RNase 7. These antibodies significantly inhibited the capacity of human stratum corneum skin extracts to control growth of P. aeruginosa. Taken together, our results indicate that P. aeruginosa induces the expression of RNase 7 in keratinocytes in an EGFR-dependent manner. Enhanced release of RNase 7 contributes to control cutaneous growth of P. aeruginosa., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 participates in innate cutaneous defense. In this review, we provide an overview about the role of RNase 7 in cutaneous defense with focus on the molecular mechanism of the antimicrobial activity of RNase 7, the regulation of RNase 7 expression, and the role of RNase 7 in skin diseases.