Site-specific O-glucosylation of the epidermal growth factor-like (EGF) repeats of notch: efficiency of glycosylation is affected by proper folding and amino acid sequence of individual EGF repeats. J Biol Chem 2012;287:33934e44.
Novel insights into the TRPV3mediated itch in atopic dermatitisTo the Editor:Chronic pruritus (itch) is a widespread and debilitating condition associated with dermatologic, systemic, neuropathic, or psychogenic disorders. The pathophysiologic mechanisms underpinning the transduction and potentiation of this refractory pruritus remain unclear. Current therapeutics are largely ineffective. 1 Thus, we have aimed to address this gap in knowledge by specifically focusing on clinically relevant intercellular communication in human skin cells, murine models of acute and chronic itch, and samples from human atopic dermatitis (AD) and psoriasis.In conditions of chronic dermatologic itch such as AD and psoriasis, certain members of the transient receptor potential (TRP) ion channel superfamily play an important role in the propagation of itch signaling. TRP vanilloid channel 3 (TRPV3) is a calcium-permeable cation channel that is abundantly expressed in epidermal keratinocytes. TRPV3 detects warm temperatures (>338C), is gated by a wide range of chemical stimuli, and plays an essential role in skin homeostasis and repair. Heatinduced activation of TRPV3 stimulates the release of a potent itch inducer, thymic stromal lymphopoietin (TSLP), from cultured murine keratinocytes. 2 In mice, intradermal injection of carvacrol, a TRPV3 agonist, elicits scratching behaviors. Gain-of-function mutations in TRPV3 have been confirmed in Olmsted syndrome, a rare pruritic genodermatosis in humans 3 and associated with AD-like inflammation in rodents. TRPV3 is upregulated in the skin of patients with AD. 2 Despite this, much remains unknown about the clinical relevance of TRPV3-linked pathways in human dermatitis and pruritus.Herein, real-time PCR was used to quantify TRPV3 expression in the skin of AD-like protease-activated receptor 2 (PAR2)overexpressing mouse (Grhl3PAR2 /1 mice). The level of TRPV3 transcripts was significantly increased in lesional skin of Grhl3PAR2 /1 mice versus in age-matched wild-type controls (Fig 1, A). Moreover, relative TRPV3 levels were significantly higher in lesional skin of Grhl3PAR2 /1 mice than in nonlesional Grhl3PAR2/ 1 mice (Fig 1, A), suggesting that TRPV3 expression is associated with the severity of dermatitis.Human skin samples were then examined to evaluate the clinical relevance of these murine findings. Specimens were collected from patients with AD (both lesional AD [LAD] and nonlesional AD [NLAD]), from patients with psoriasis (both lesional psoriasis [LPS] and nonlesional psoriasis [NLPS]), and from healthy controls (HC). All were analyzed by RNA sequencing, with data indicating the mean change in transcript level relative to HC. In LAD samples, TRPV3 was the only member of the TRPV family to be upregulated, with transcripts showing greater than a 2-fold increase over the HC levels (Fig 1, B). Similar to our murine model, this upregulation was absent in NLAD skin (Fig 1, C). Levels of TRPV3 transcripts were also increased in LPS skin samples versus in HC skin samples, but not in NLPS sample...
The microbial community exhibits remarkable diversity on topographically distinct skin regions, which may be accompanied by differences in skin immune characteristics. Our aim was to compare the immune milieu of healthy sebaceous gland rich (SGR) and sebaceous gland poor (SGP) skin areas, and to analyze its changes in an inflammatory disease of SGR skin. For this purpose, immunohistochemical, immunocytochemical and quantitative real-time PCR analyses of thymic stromal lymphopoietin (TSLP) and other cytokines, phenotypic immune cell markers and transcription factors were carried out in samples from SGP, SGR skin and from papulopustular rosacea (PPR). TSLP mRNA and protein production was also studied in cultured keratinocytes. In SGR skin, higher TSLP expression, dendritic cell (DC) appearance without prominent activation and T cell presence with interleukin (IL)-17/IL-10 cytokine milieu were detected compared to SGP skin. Linoleic acid, a major sebum component, was found to induce TSLP expression dose-dependently in keratinocytes. In PPR, significantly decreased TSLP level and influx of inflammatory DCs and T cells with IL-17/interferon-γ cytokine milieu were observed. According to our results, SGR skin is characterized by a distinct, non-inflammatory immune surveillance, which may explain the preferred localization of inflammatory skin diseases, and can influence future barrier repair therapeutic concepts.3
Rosacea is a common chronic inflammation of sebaceous glanderich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased hydration levels. Until now, there has been no thorough molecular analysis of permeability barrier alterations in the skin of patients with rosacea. Thus, we aimed to investigate the barrier alterations in papulopustular rosacea samples compared with healthy sebaceous glanderich skin, using RNA sequencing analysis (n ¼ 8). Pathway analyses by Cytoscape ClueGO revealed 15 significantly enriched pathways related to skin barrier formation. RT-PCR and immunohistochemistry were used to validate the pathway analyses. The results showed significant alterations in barrier components in papulopustular rosacea samples compared with sebaceous glanderich skin, including the cornified envelope and intercellular lipid lamellae formation, desmosome and tight junction organizations, barrier alarmins, and antimicrobial peptides. Moreover, the barrier damage in papulopustular rosacea was unexpectedly similar to atopic dermatitis; this similarity was confirmed by immunofluorescent staining. In summary, besides the well-known dysregulation of immunological, vascular, and neurological functions, we demonstrated prominent permeability barrier alterations in papulopustular rosacea at the molecular level, which highlight the importance of barrier repair therapies for rosacea.
The immunological barrier of the healthy skin is considered to be unified on the whole body surface—however, recent indirect findings have challenged this dogma since microbial and chemical milieu (e.g., sebum, sweat, and pH) exhibit remarkable differences on topographically distinct skin areas. Therefore, in the present study, we performed whole transcriptomic and subsequent pathway analyses to assess differences between sebaceous gland rich (SGR) and sebaceous gland poor (SGP) regions. Here, we provide the first evidence that different skin regions exhibit a characteristic innate and adaptive immune and barrier milieu as we could detect significantly increased chemokine (CCL2, 3, 19, 20, 23, 24) and antimicrobial peptide (S100A7, A8, A9, lipocalin, β-defensin-2) expression, altered barrier (keratin 17, 79) functions, and a non-inflammatory Th17/IL-17 dominance in SGR skin compared to SGP. Regarding pro-inflammatory molecules (IL-1α, IL-6, IL-8, IL-33, TNF-α), similarly low levels were detected in both regions. Our data may explain the characteristic topographical localization of some immune-mediated and autoimmune skin disorders and we also propose that the term “healthy skin control sample,” widely used in experimental Dermatology, should only be accepted if researchers carefully specify the exact region of the healthy skin (along with the site of the diseased sample).
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