The Experts below are selected from a list of 12213 Experts worldwide ranked by ideXlab platform

Cristiano Rumio - One of the best experts on this subject based on the ideXlab platform.

  • low molecular weight hyaluronic acid increases the self defense of Skin Epithelium by induction of β defensin 2 via tlr2 and tlr4
    Journal of Immunology, 2008
    Co-Authors: Silvia Gariboldi, Marco Palazzo, Laura Zanobbio, Silvia Selleri, Michele Sommariva, Lucia Sfondrini, Stefano Cavicchini, Andrea Balsari, Cristiano Rumio
    Abstract:

    In sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. We found that LMW-HA induces activation of keratinocytes, which respond by producing beta-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-alpha, IL-1beta, or IL-6 was observed. Ex vivo and in vivo treatments of murine Skin with LMW-HA showed a release of mouse beta-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release beta-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, our observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of beta-defensins by keratinocytes, thus ameliorating the self-defense of the Skin for the protection of cutaneous tissue from infection by microorganisms.

  • low molecular weight hyaluronic acid increases the self defense of Skin Epithelium by induction of β defensin 2 via tlr2 and tlr4
    Journal of Immunology, 2008
    Co-Authors: Silvia Gariboldi, Marco Palazzo, Laura Zanobbio, Silvia Selleri, Michele Sommariva, Lucia Sfondrini, Stefano Cavicchini, Andrea Balsari, Cristiano Rumio
    Abstract:

    In sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. We found that LMW-HA induces activation of keratinocytes, which respond by producing β-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-α, IL-1β, or IL-6 was observed. Ex vivo and in vivo treatments of murine Skin with LMW-HA showed a release of mouse β-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release β-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, our observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of β-defensins by keratinocytes, thus ameliorating the self-defense of the Skin for the protection of cutaneous tissue from infection by microorganisms.

Elaine Fuchs - One of the best experts on this subject based on the ideXlab platform.

  • abstract ia04 stem cells coping with stress and cancer
    Cancer Research, 2020
    Co-Authors: Elaine Fuchs
    Abstract:

    Adult tissue stem cells have the ability to self-renew long term and differentiate into one or more tissues. Many stem cells are used sparingly to replenish cells during normal homeostasis. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. The regulatory circuitry governing this normal balancing act must be intricately regulated in normal homeostasis and then transiently altered to cope with injury responses. Increasing evidence suggests that the mechanism goes awry in inflammation and becomes hijacked in cancers. Skin Epithelium is an excellent model system to understand how stem cells remain quiescent during times of minimal wear and tear, how these cells become mobilized during the cyclical bouts of hair growth and wound repair, and how the normal process of stem cell activation goes awry in cancer and inflammation. We have identified and characterized at a molecular level the Skin’s stem cells and shown that they reside in distinct niches that impart to the stem cells their behavior both in task and in the molecular properties they display. We use high-throughput genetic and genomic approaches to dissect at a molecular level how stem cell interactions with their niches differ in homeostasis, wound repair, and inflammation, and how heterogeneity in the tumor microenvironment can confer on stem cells resistance to chemotherapy and immunotherapy. Our global objective is to apply our knowledge of the basic science of epithelial stem cells to unfold new avenues for therapeutics. Citation Format: Elaine Fuchs. Stem cells: Coping with stress and cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA04.

  • stem cells of the Skin Epithelium
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Laura C Alonso, Elaine Fuchs
    Abstract:

    Tissue stem cells form the cellular base for organ homeostasis and repair. Stem cells have the unusual ability to renew themselves over the lifetime of the organ while producing daughter cells that differentiate into one or multiple lineages. Difficult to identify and characterize in any tissue, these cells are nonetheless hotly pursued because they hold the potential promise of therapeutic reprogramming to grow human tissue in vitro, for the treatment of human disease. The mammalian Skin Epithelium exhibits remarkable turnover, punctuated by periods of even more rapid production after injury due to burn or wounding. The stem cells responsible for supplying this tissue with cellular substrate are not yet easily distinguishable from neighboring cells. However, in recent years a significant body of work has begun to characterize the Skin epithelial stem cells, both in tissue culture and in mouse and human Skin. Some epithelial cells cultured from Skin exhibit prodigious proliferative potential; in fact, for >20 years now, cultured human Skin has been used as a source of new Skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of stem cells. Cell fate choices, including both self-renewal and differentiation, are crucial biological features of stem cells that are still poorly understood. Skin epithelial stem cells represent a ripe target for research into the fundamental mechanisms underlying these important processes.

  • a developmental conundrum a stabilized form of β catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells
    Journal of Cell Biology, 2002
    Co-Authors: Ramanuj Dasgupta, Horace Rhee, Elaine Fuchs
    Abstract:

    Wnt signaling orchestrates morphogenetic processes in which changes in gene expression are associated with dramatic changes in cell organization within developing tissue/organss. Upon signaling, excess β-catenin not utilized at cell–cell junctions becomes stabilized, where it can provide the transcriptional activating domain for Lef/Tcf DNA binding proteins. In Skin Epithelium, forced stabilization of β-catenin in epidermis promotes hair follicle morphogenesis, whereas conditional removal of β-catenin in hair progenitor cells specifies an epidermal fate. We now report that a single protein, a stabilized version of β-catenin lacking the COOH-terminal transactivation domain, acts in epidermis to promote hair fates and in hair cells to promote epidermal fate. This reveals fundamental differences in ways that epidermal and hair cells naturally respond to β-catenin signaling. In exploring the phenotype, we uncovered mechanistic insights into the complexities of Lef1/Tcf/β-catenin signaling. Importantly, how a cell will respond to the transgene product, where it will be localized, and whether it can lead to activation of endogenous β-catenin/Tcf/Lef complexes is specifically tailored to Skin stem cells, their particular lineage and their relative stage of differentiation. Finally, by varying the level of β-catenin signaling during a cell fate program, the Skin cell appears to be pliable, switching fates multiple times.

  • rescuing desmoplakin function in extra embryonic ectoderm reveals the importance of this protein in embryonic heart neuroEpithelium Skin and vasculature
    Development, 2001
    Co-Authors: G I Gallicano, Christoph Bauer, Elaine Fuchs
    Abstract:

    Desmosomes mediate intercellular adhesion through desmosomal cadherins, which interface with plakoglobin (PG) and desmoplakin (DP) to associate with the intermediate filament (IF) cytoskeleton. Desmosomes first assemble in the E3.5 mouse trophectoderm, concomitant with establishment of epithelial polarity and appearance of a blastocoel cavity. Increasing in size and number, desmosomes continue their prominence in extra-embryonic tissues, but as development proceeds, they also become abundant in a number of embryonic tissues, including heart muscle, epidermis and neuroEpithelium. Previously, we explored the functional importance of desmosomes by ablating the Dsp gene. Homozygous Dsp mutant embryos progressed through implantation, but did not survive beyond E6.5, owing to a loss or instability of desmosomes and tissue integrity. We have now rescued the extra-embryonic tissues by aggregation of tetraploid (wild-type) and diploid (Dsp mutant) morulae. These animals survive several days longer, but die shortly after gastrulation, with major defects in the heart muscle, neuroEpithelium and Skin Epithelium, all of which possess desmosomes, as well as the microvasculature, which does not. Interestingly, although wild-type endothelial cells of capillaries do not form desmosomes, they possess unusual intercellular junctions composed of DP, PG and VE-cadherin. The severity in phenotype and the breadth of defects in the Dsp mutant embryo is greater than PG mutant embryos, substantiating redundancy between PG and other armadillo proteins (e.g. beta-catenin). The timing of lethality is similar to that of the VE-cadherin null embryo, suggesting that a participating cause of death may be a defect in vasculature, not reported for PG null embryos.

  • conditional ablation of β1 integrin in Skin severe defects in epidermal proliferation basement membrane formation and hair follicle invagination
    Journal of Cell Biology, 2000
    Co-Authors: Srikala Raghavan, Christoph Bauer, Gina Mundschau, Elaine Fuchs
    Abstract:

    The major epidermal integrins are α3β1 and hemidesmosome-specific α6β4; both share laminin 5 as ligand. Keratinocyte culture studies implicate both integrins in adhesion, proliferation, and stem cell maintenance and suggest unique roles for αβ1 integrins in migration and terminal differentiation. In mice, however, whereas ablation of α6 or β4 results in loss of hemidesmosomes, epidermal polarity, and basement membrane (BM) attachment, ablation of α3 only generates microblistering due to localized internal shearing of BM. Using conditional knockout technology to ablate β1 in Skin Epithelium, we have uncovered biological roles for αβ1 integrins not predicted from either the α3 knockout or from in vitro studies. In contrast to α3 null mice, β1 mutant mice exhibit severe Skin blistering and hair defects, accompanied by massive failure of BM assembly/organization, hemidesmosome instability, and a failure of hair follicle keratinocytes to remodel BM and invaginate into the dermis. Although epidermal proliferation is impaired, a spatial and temporal program of terminal differentiation is executed. These results indicate that β1's minor partners in Skin are important, and together, αβ1 integrins are required not only for extracellular matrix assembly but also for BM formation. This, in turn, is required for hemidesmosome stability, epidermal proliferation, and hair follicle morphogenesis. However, β1 downregulation does not provide the trigger to terminally differentiate.

Ralf Paus - One of the best experts on this subject based on the ideXlab platform.

  • the frog Skin derived antimicrobial peptide esculentin 1a 1 21 nh2 promotes the migration of human hacat keratinocytes in an egf receptor dependent manner a novel promoter of human Skin wound healing
    PLOS ONE, 2015
    Co-Authors: Antonio Di Grazia, Ralf Paus, Floriana Cappiello, Akiko Imanishi, Arianna Mastrofrancesco, Mauro Picardo, Maria Luisa Mangoni
    Abstract:

    One of the many functions of Skin is to protect the organism against a wide range of pathogens. Antimicrobial peptides (AMPs) produced by the Skin Epithelium provide an effective chemical shield against microbial pathogens. However, whereas antibacterial/antifungal activities of AMPs have been extensively characterized, much less is known regarding their wound healing-modulatory properties. By using an in vitro re-epithelialisation assay employing special cell-culture inserts, we detected that a derivative of the frog-Skin AMP esculentin-1a, named esculentin-1a(1-21)NH2, significantly stimulates migration of immortalized human keratinocytes (HaCaT cells) over a wide range of peptide concentrations (0.025–4 μM), and this notably more efficiently than human cathelicidin (LL-37). This activity is preserved in primary human epidermal keratinocytes. By using appropriate inhibitors and an enzyme-linked immunosorbent assay we found that the peptide-induced cell migration involves activation of the epidermal growth factor receptor and STAT3 protein. These results suggest that esculentin-1a(1-21)NH2 now deserves to be tested in standard wound healing assays as a novel candidate promoter of Skin re-epithelialisation. The established ability of esculentin-1a(1-21)NH2 to kill microbes without harming mammalian cells, namely its high anti-Pseudomonal activity, makes this AMP a particularly attractive candidate wound healing promoter, especially in the management of chronic, often Pseudomonas-infected, Skin ulcers.

  • Deciphering the functions of the hair follicle infundibulum in Skin physiology and disease
    Cell and Tissue Research, 2014
    Co-Authors: Marlon R. Schneider, Ralf Paus
    Abstract:

    The infundibulum is the funnel-shaped, uppermost epithelial segment of the hair follicle. Thus, as the infundibulum represents a major interface zone of mammalian Skin Epithelium with the environment and harbors a rich residential microflora, it is not surprising that this area is endowed with a specialized immune system and innate immune defenses. Clinically, the infundibulum is quite important, as it becomes prominently involved in many Skin diseases such as acne, infundibular folliculitis and cysts, hidradenitis suppurativa, keratosis pilaris, Fox-Fordyce disease, and a subtype of basal cell carcinoma. Nevertheless, the biology of the infundibulum is only poorly understood, and it remains largely unknown how exactly the infundibulum contributes to Skin disease, and how it might be targeted effectively for treating important Skin diseases. Several recent studies in mouse models have identified new potential infundibular markers, shed light upon infundibular development and homeostasis, identified infundibular epithelial stem cells, and have implicated the infundibulum in the pathogenesis of additional Skin disorders. These recent insights encourage one to systematically re-visit the biology and pathology of the infundibulum, one of the most important, yet least-studied frontiers in mammalian epithelial physiology.

  • a novel control of human keratin expression cannabinoid receptor 1 mediated signaling down regulates the expression of keratins k6 and k16 in human keratinocytes in vitro and in situ
    PeerJ, 2013
    Co-Authors: Yuval Ramot, Koji Sugawara, Nora Zakany, Balazs Istvan Toth, Tamas Biro, Ralf Paus
    Abstract:

    Cannabinoid receptors (CB) are expressed throughout human Skin Epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory Skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human Skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA), decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression.

  • runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse Skin
    Molecular and Cellular Biology, 2010
    Co-Authors: Charlene S L Hoi, Ralf Paus, Song Eun Lee, David J Mcdermitt, Karen M Osorio, Caroline M Piskun, Rachel M Peters, Tudorita Tumbar
    Abstract:

    Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced Skin tumorigenesis in mice turned on broad Runx1 expression in regions of the Skin Epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a Skin oncogene by directly promoting proliferation of the epithelial cells.

  • towards the development of a simplified long term organ culture method for human scalp Skin and its appendages under serum free conditions
    Experimental Dermatology, 2007
    Co-Authors: Sybille Hasse, Eniko Bodo, Christian Rose, Wolfgang Funk, Ralf Paus
    Abstract:

    Organ culture of human scalp Skin is usually performed with serum-containing medium, which limits its analytical usefulness. Here we report that intact human scalp Skin can be grown at the air/liquid interface in supplemented, serum-free William's E medium for more than 2 weeks. Active hair shaft growth was visible until day 16 and was significantly enhanced compared with minimum essential medium (MEM) + 10% fetal bovine serum (FBS). Moreover, William's E medium protected better against cell death than MEM + 10% FBS before day 12. Using quantitative immunochemistry, proliferating (Ki-67+) cells could still be observed in the Epithelium of hair follicles even on day 17 of serum-free Skin organ culture. The number of apoptotic (TUNEL+) cells in the Skin Epithelium rose steadily after day 5. Giemsa stains revealed mature Skin mast cells even after 13 days in culture. The percentage of surviving hair follicles (mostly with catagen- or telogen-like morphology) gradually increased over time displaying mostly catagen hair follicles after 17 days of culture. Although epidermis and hair follicle Epithelium showed increasing atrophy and degeneration, and their pigmentation decreased gradually over time, some long-term-surviving epithelial islands were found in association with remnants of follicular structures as late as on day 88. These preliminary data suggest that a very simple serum-free organ culture method allows prolonged human Skin and hair follicle survival as well as some limited hair follicle cycling in intact Skin for more than 2 weeks under well-defined experimental conditions. This pragmatic assay invites multiple uses, and may become a valuable tool for both Skin and hair research.

Axel Schweickert - One of the best experts on this subject based on the ideXlab platform.

  • a novel serotonin secreting cell type regulates ciliary motility in the mucociliary epidermis of xenopus tadpoles
    Development, 2014
    Co-Authors: Peter Walentek, Susanne Bogusch, Thomas Thumberger, Philipp Vick, Eamon Dubaissi, Tina Beyer, Martin Blum, Axel Schweickert
    Abstract:

    The embryonic Skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway Epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval Skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the Skin Epithelium. This effect was mediated by serotonin type 3 receptor (Htr3), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval Skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic Skin as a model system for human MCEs, which have been known for serotonin-dependent regulation of ciliary beat frequency.

  • a novel serotonin secreting cell type regulates ciliary motility in the mucociliary epidermis of xenopus tadpoles
    Development, 2014
    Co-Authors: Peter Walentek, Susanne Bogusch, Thomas Thumberger, Philipp Vick, Eamon Dubaissi, Tina Beyer, Martin Blum, Axel Schweickert
    Abstract:

    The embryonic Skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway Epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval Skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the Skin Epithelium. This effect was mediated by serotonin type 3 receptor ( Htr3 ), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval Skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic Skin as a model system for human MCEs, which have been known for serotonin-dependent regulation of ciliary beat frequency.

Silvia Gariboldi - One of the best experts on this subject based on the ideXlab platform.

  • low molecular weight hyaluronic acid increases the self defense of Skin Epithelium by induction of β defensin 2 via tlr2 and tlr4
    Journal of Immunology, 2008
    Co-Authors: Silvia Gariboldi, Marco Palazzo, Laura Zanobbio, Silvia Selleri, Michele Sommariva, Lucia Sfondrini, Stefano Cavicchini, Andrea Balsari, Cristiano Rumio
    Abstract:

    In sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. We found that LMW-HA induces activation of keratinocytes, which respond by producing beta-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-alpha, IL-1beta, or IL-6 was observed. Ex vivo and in vivo treatments of murine Skin with LMW-HA showed a release of mouse beta-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release beta-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, our observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of beta-defensins by keratinocytes, thus ameliorating the self-defense of the Skin for the protection of cutaneous tissue from infection by microorganisms.

  • low molecular weight hyaluronic acid increases the self defense of Skin Epithelium by induction of β defensin 2 via tlr2 and tlr4
    Journal of Immunology, 2008
    Co-Authors: Silvia Gariboldi, Marco Palazzo, Laura Zanobbio, Silvia Selleri, Michele Sommariva, Lucia Sfondrini, Stefano Cavicchini, Andrea Balsari, Cristiano Rumio
    Abstract:

    In sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. We found that LMW-HA induces activation of keratinocytes, which respond by producing β-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-α, IL-1β, or IL-6 was observed. Ex vivo and in vivo treatments of murine Skin with LMW-HA showed a release of mouse β-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release β-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, our observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of β-defensins by keratinocytes, thus ameliorating the self-defense of the Skin for the protection of cutaneous tissue from infection by microorganisms.