de Koning, HD, Rodijk-Olthuis, D, van Vlijmen-Willems, IM, Joosten, LA, Netea, MG, Schalkwijk, J et al.. A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis. J Invest Dermatol 130: 2611-2620
Human epidermis plays an important role in host defense by acting as a physical barrier and signaling interface between the environment and the immune system. Pattern recognition receptors (PRRs) are crucial to maintain homeostasis and provide protection during infection, but are also causally involved in monogenic auto-inflammatory diseases. This study aimed to investigate the epidermal expression of PRRs and several associated host defense molecules in healthy human skin, psoriasis, and atopic dermatitis (AD). Using microarray analysis and real-time quantitative PCR, we found that many of these genes are transcribed in normal human epidermis. Only a few genes were differentially induced in psoriasis (CLEC7A (dectin-1), Toll-like receptor (TLR) 4, and mannose receptor C type 1 (MRC1)) or AD (MRC1, IL1RN, and IL1β) compared with normal epidermis. A remarkably high expression of dectin-1 mRNA was observed in psoriatic epidermis and this was corroborated by immunohistochemistry. In cultured primary human keratinocytes, dectin-1 expression was induced by IFN-γ, IFN-α, and Th17 cytokines. Keratinocytes were unresponsive, however, to dectin-1 ligands such as β-glucan or heat-killed Candida albicans, nor did we observe synergy with TLR2/TLR5 ligands. In conclusion, upregulation of dectin-1 in psoriatic lesions seems to be under control of psoriasis-associated cytokines. Its role in the biology of skin inflammation and infection remains to be explored.
"Speculatively, this may lead to abnormal exposure of the epidermal keratinocytes or Langerhans cells to live bacteria or bacterial components. Continuous exposure to pathogen-associated molecular patterns (PAMPs) may lead to uncontrolled stimulation of pattern recognition receptors (PRR) some of which were shown to be abnormally expressed in lesional psoriasis skin . Stimulation of the innate and adaptive immune system by PAMPs or by specific antigens could be a driving force for the chronic inflammatory process, but such a scenario clearly requires experimental confirmation. "
[Show abstract][Hide abstract] ABSTRACT: Background
Recent advances in sequencing technologies have enabled metagenomic analyses of many human body sites. Several studies have catalogued the composition of bacterial communities of the surface of human skin, mostly under static conditions in healthy volunteers. Skin injury will disturb the cutaneous homeostasis of the host tissue and its commensal microbiota, but the dynamics of this process have not been studied before. Here we analyzed the microbiota of the surface layer and the deeper layers of the stratum corneum of normal skin, and we investigated the dynamics of recolonization of skin microbiota following skin barrier disruption by tape stripping as a model of superficial injury.
We observed gender differences in microbiota composition and showed that bacteria are not uniformly distributed in the stratum corneum. Phylogenetic distance analysis was employed to follow microbiota development during recolonization of injured skin. Surprisingly, the developing neo-microbiome at day 14 was more similar to that of the deeper stratum corneum layers than to the initial surface microbiome. In addition, we also observed variation in the host response towards superficial injury as assessed by the induction of antimicrobial protein expression in epidermal keratinocytes.
We suggest that the microbiome of the deeper layers, rather than that of the superficial skin layer, may be regarded as the host indigenous microbiome. Characterization of the skin microbiome under dynamic conditions, and the ensuing response of the microbial community and host tissue, will shed further light on the complex interaction between resident bacteria and epidermis.
"Furthermore, although the fungal PAMPs inducing cytokine responses in myeloid cells are well described, including mannans and β-glucans, we found that none of these PAMPs or the other polysaccharide constituent of the fungal cell wall, chitin, induced cytokine responses in oral ECs . This was also recently demonstrated for skin keratinocytes . Together, these studies suggest that ECs may utilize different receptors for immune activation and/or target different fungal moieties than myeloid cells, indicating that epithelial fungal detection mechanisms may differ from myeloid cell detection mechanisms. "
[Show abstract][Hide abstract] ABSTRACT: Interactions between mucosal surfaces and microbial microbiota are key to host defense, health, and disease. These surfaces are exposed to high numbers of microbes and must be capable of distinguishing between those that are beneficial or avirulent and those that will invade and cause disease. Our understanding of the mechanisms involved in these discriminatory processes has recently begun to expand as new studies bring to light the importance of epithelial cells and novel immune cell subsets such as T(h)17 T cells in these processes. Elucidating how these mechanisms function will improve our understanding of many diverse diseases and improve our ability to treat patients suffering from these conditions. In our voyage to discover these mechanisms, mucosal interactions with opportunistic commensal organisms such as the fungus Candida albicans provide insights that are invaluable. Here, we review current knowledge of the interactions between C. albicans and epithelial surfaces and how this may shape our understanding of microbial-mucosal interactions.
"Furthermore, blockage of Dectin-1 could prevent experimental autoimmune uveoretinitis, a Th1/Th17 disease . High expression of Dectin-1 mRNA was also observed in patients with psoriais . These studies imply that dectin-1 plays a pivotal role in the innate immune system and is able to modulate adaptive immune responses, of which, especially Th17 responses are implicated in immunopathology. "
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells capture antigens through PRRs and modulate adaptive immune responses. The type of adaptive immune T cell response generated is dependent upon the type of PRR activated by the microbes. Dectin-1 is a C-type lectin receptor present on dendritic cells.
Here we show that selective dectin-1 agonist Curdlan can activate human DCs and induce the secretion of large amounts of IL-23, IL-1β, IL-6 and low levels of IL-12p70 as determined by ELISA. The Curdlan-stimulated DCs are efficient at priming naïve CD4 cells to differentiate into Th17 and Th1 cells. Furthermore, these CD4 T cells induce differentiation of B cells to secrete IgG and IgA. In addition, Curdlan-stimulated DCs promote the expansion and differentiation of Granzyme and perforin expressing cytotoxic T lymphocyte that display high cytolytic activity against target tumor cells in vitro.
These data demonstrate that DCs stimulated through Dectin-1 can generate efficient Th, CTL and B cell responses and can therefore be used as effective mucosal and systemic adjuvants in humans.
PLoS ONE 10/2010; 5(10):e13418. DOI:10.1371/journal.pone.0013418 · 3.23 Impact Factor
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