Background Suppression of the adaptive immune system by UV radiation plays an important role in photocarcinogenesis. Exacerbation of skin infections has been proposed as a further consequence of ...UV-induced immunosuppression. Clinically bacterial infections are not a problem. For defense against bacteria, the innate immune response including the release of antimicrobial peptides is much more relevant than the adaptive immune response. Keratinocytes have the capacity to release antimicrobial peptides. Objective We asked whether UV radiation induces antimicrobial peptides in vitro and in vivo. Methods Antimicrobial peptide expression by normal human keratinocytes was measured by real-time PCR and fluorescence-activated cell sorting analysis. Biopsies taken from human volunteers and skin explants were studied with immunohistochemistry. Results Real-time PCR of normal human keratinocytes revealed a dose-dependent increase of human β-defensin-2, -3, ribonuclease 7, and psoriasin (S100A7) after UV radiation. This was confirmed at the protein level by intracellular fluorescence-activated cell sorting and in vitro immunofluorescence analysis. Immunohistochemistry of biopsies taken from healthy volunteers exposed to different UV radiation doses revealed enhanced epidermal expression of antimicrobial peptides after UV exposure. This was also confirmed by exposing human skin explants to UV radiation. Conclusion UV radiation exerts diverse effects on the immune system, suppressing the adaptive but inducing the innate immune response. This may explain why T-cell–mediated immune reactions are suppressed on UV exposure but not host defense reactions against bacterial attacks.
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.
Skin microbiota and human 3D skin models Rademacher, Franziska; Simanski, Maren; Gläser, Regine ...
Experimental dermatology,
20/May , Letnik:
27, Številka:
5
Journal Article
Recenzirano
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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.
The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β ...is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.
Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. ...coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human skin can defend itself against potentially invading microorganisms by production of antimicrobial peptides (AMPs). The expression of AMPs in atopic dermatitis (AD) is still emerging. To gain ...more insight into the role of AMPs in AD, we systematically analyzed the expression of ribonuclease 7 (RNase 7), psoriasin, and human β-defensins (hBD)-2 and -3 in AD compared with psoriatic and healthy control skin as well as after experimental barrier disruption. Immunostaining revealed enhanced expression of all AMPs in the lesional skin of untreated AD and psoriasis when compared with non-lesional skin and controls. Accordingly, induced in vivo secretion of RNase 7, psoriasin, and hBD-2 was detected using ELISA on lesional skin in AD and in even higher concentrations in psoriasis. The secretion of AMPs did not correlate with severity of AD and Staphylococcus aureus colonization. Skin barrier disruption caused enhanced immunoreactivity of hBD-2 and hBD-3 after 24hours. Strong secretion of RNase 7 was already detected after 1hour, whereas hBD-2 secretion was significantly enhanced after 24hours only under occlusion. Thus, a disturbed skin barrier may trigger AMP induction in AD and psoriasis. The functional role of AMP in AD, especially with regard to the control of S. aureus colonization, needs further analysis.
Genes of the S100 fused-type protein (SFTP) family are clustered within the epidermal differentiation complex and encode essential components that maintain epithelial homeostasis and barrier ...functions. Recent genetic studies have shown that mutations within the gene encoding the SFTP filaggrin cause ichthyosis vulgaris and are major predisposing factors for atopic dermatitis. As a vital component of healthy skin, filaggrin is also a precursor of natural moisturizing factors. Here we present the discovery of a member of this family, designated as filaggrin-2 (FLG2) that is expressed in human skin. The FLG2 gene encodes a histidine- and glutamine-rich protein of approximately 248 kDa, which shares common structural features with other SFTP members, in particular filaggrin. We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta. In cultured primary keratinocytes, FLG2 mRNA expression displayed almost the same kinetics as that of filaggrin following Ca(2+) stimulation, suggesting an important role in molecular regulation of epidermal terminal differentiation. We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis. Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bullous pemphigoid (BP) is the most common autoimmune blistering disease in Europe. As both the incidence of the disease and the relative proportion of the elderly population continue to rise, it ...represents a significant medical burden. Whereas some progress has been achieved in defining genetic risk factors for autoimmune blistering diseases, no environmental agent has been conclusively identified. Emerging evidence suggests that host immunity may influence the skin microbiota, while the latter modulates cutaneous immunity. Nevertheless, the relationship between skin microbial communities and autoimmune bullous disease has yet to be studied in humans. Here, we aim to characterise and compare the skin microbiome of patients with BP and healthy, age‐matched controls at numerous body sites. Similar to what has been shown in healthy controls, the composition of skin microbiota in patients with BP appears to be very divergent and site specific. Microbial phylum abundances differ between perilesional sites of patients with BP and the same anatomic locations of control patients. A distinct cutaneous microbiota profile, which correlates with BP, further strengthens the significance of commensal‐host interaction on our immune system. Moreover, these results raise the possibility that the cutaneous microbiome may contribute to the pathogenesis of BP, with important implications for the treatment of this disease.
Background Antimicrobial peptides (AMPs) are small effector molecules of the innate immune system with well-known antimicrobial activity. Skin infections rarely occur in patients with cutaneous lupus ...erythematosus (CLE), and AMP expression in CLE has not been previously evaluated. Objectives We aimed to determine the expression of several important AMPs in 3 different subtypes of CLE. Methods Skin lesions were analyzed for the gene and protein expression of human β-defensin (hBD)-1, -2, and -3; RNase-7; the cathelicidin LL-37; and psoriasin (S100A7) using real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Results Skin biopsy specimens of 96 study participants including 47 patients with CLE (15 patients with discoid lupus erythematosus LE, 11 patients with subacute CLE, and 21 patients with LE tumidus), 34 patients with psoriasis, and 15 healthy control subjects were evaluated in this study. HBD-2, hBD-3, LL-37, and psoriasin were significantly more highly expressed in CLE as compared with healthy controls, and most AMPs were significantly more highly induced in subacute CLE as compared with discoid LE and LE tumidus. AMP gene expression paralleled well with AMP protein expression in CLE and controls. Subacute CLE and discoid LE showed a similar correlation of AMP gene expression (significant correlations between hBD-1 and RNase-7, hBD-2 and hBD-3, hBD-2 and psoriasin, and hBD-3 and psoriasin). Limitations The relatively small number of samples and the lack of analysis of the lesional bacterial colonization are a limitation. Conclusions Several AMPs are increased in CLE at both gene and protein levels. This could explain the low prevalence of skin infections in CLE. It remains to be elucidated whether AMPs play a pathogenic role in CLE.
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