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Quantitation of the Staining Intensity Using Five Different Antibodies on Three Different Skin Phenotypes
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Psoriasis shares many features with wound healing, a process that involves switching keratinocytes from growth to differentiation. Ca2+ is known to regulate this process. The N-methyl-d-aspartate receptor (NMDAR), an ionotropic glutamate receptor found on keratinocytes, is expressed abnormally in psoriasis in vivo.
The goals of this study are to de...
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... with the antibodies against NR1, NR2A, NR2B, NR2C and NR2D demonstrated that all four subunits including NR1 were expressed in all the layers of the normal, involved and uninvolved epidermis [ Fig. 2]. Quantification of the extent of strong, medium and weak immunostaining showed differences in the staining pattern for the three skin phenotypes, but most differences did not reach statistical significance (p<0.05) [Fig. 3]. However, the percent strong staining for NR2C was significantly less in the cells in the basal cell layer of involved epidermis compared with the cells in the basal cell layer of normal epidermis (p<0.02, ANOVA) [Fig. 3]. Cells in the basal cell layer of the uninvolved epidermis also showed significantly less percent strong staining for NR2C than the cells in the basal layer of normal epidermis (p<0.02, ANOVA) [ Fig. 3]. In contrast, cells in the basal cell layer of the uninvolved epidermis showed a significantly greater percent strong staining for NR2D compared to cells in the basal cell layer of normal epidermis (p<0.001, ANOVA) Thus, the basal cell layer of both the involved and uninvolved epidermis showed differences in the level of NMDAR subunit expression compared to the basal cell layer of normal epidermis, a difference that may relate to the increased rate of wound healing found in both the involved and uninvolved skin in ...
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... with the antibodies against NR1, NR2A, NR2B, NR2C and NR2D demonstrated that all four subunits including NR1 were expressed in all the layers of the normal, involved and uninvolved epidermis [ Fig. 2]. Quantification of the extent of strong, medium and weak immunostaining showed differences in the staining pattern for the three skin phenotypes, but most differences did not reach statistical significance (p<0.05) [Fig. 3]. However, the percent strong staining for NR2C was significantly less in the cells in the basal cell layer of involved epidermis compared with the cells in the basal cell layer of normal epidermis (p<0.02, ANOVA) [Fig. 3]. Cells in the basal cell layer of the uninvolved epidermis also showed significantly less percent strong staining for NR2C than the cells in the basal layer of normal epidermis (p<0.02, ANOVA) [ Fig. 3]. In contrast, cells in the basal cell layer of the uninvolved epidermis showed a significantly greater percent strong staining for NR2D compared to cells in the basal cell layer of normal epidermis (p<0.001, ANOVA) Thus, the basal cell layer of both the involved and uninvolved epidermis showed differences in the level of NMDAR subunit expression compared to the basal cell layer of normal epidermis, a difference that may relate to the increased rate of wound healing found in both the involved and uninvolved skin in ...
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... that all four subunits including NR1 were expressed in all the layers of the normal, involved and uninvolved epidermis [ Fig. 2]. Quantification of the extent of strong, medium and weak immunostaining showed differences in the staining pattern for the three skin phenotypes, but most differences did not reach statistical significance (p<0.05) [Fig. 3]. However, the percent strong staining for NR2C was significantly less in the cells in the basal cell layer of involved epidermis compared with the cells in the basal cell layer of normal epidermis (p<0.02, ANOVA) [Fig. 3]. Cells in the basal cell layer of the uninvolved epidermis also showed significantly less percent strong staining ...
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... in the cells in the basal cell layer of involved epidermis compared with the cells in the basal cell layer of normal epidermis (p<0.02, ANOVA) [Fig. 3]. Cells in the basal cell layer of the uninvolved epidermis also showed significantly less percent strong staining for NR2C than the cells in the basal layer of normal epidermis (p<0.02, ANOVA) [ Fig. 3]. In contrast, cells in the basal cell layer of the uninvolved epidermis showed a significantly greater percent strong staining for NR2D compared to cells in the basal cell layer of normal epidermis (p<0.001, ANOVA) Thus, the basal cell layer of both the involved and uninvolved epidermis showed differences in the level of NMDAR subunit ...
Citations
... As the histological analysis of recovering human and mouse wounds indicated that OLFM4 was induced at the proliferative phase of wound healing, we next sought to investigate whether its expression pattern was altered in skin disorders. Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation [25] and is accompanied by accelerated wound healing [26]. Examination of OLFM4 expression in psoriatic lesional skin showed increased levels of the protein in epidermis compared to healthy skin (Fig. 3A, B). ...
... As our in vitro and in vivo experiments demonstrated that OLFM4 promoted keratinocyte proliferation and wound healing it is possible that this protein may participate in the pathogenesis of psoriasis by contributing to the maintenance of keratinocyte hyperproliferation in psoriatic skin lesions. Furthermore, the fact that cutaneous wounds heal faster in psoriatic skin [26] correlated well with the increased OLFM4 expression in the lesional skin areas. Moreover, molecular pathway analysis suggested that OLFM4 may mediate the reduction of tumour suppressor PTEN expression and it has been shown that PTEN expression is downregulated in psoriatic lesions [38]. ...
Olfactomedin-4 (OLFM4) is an olfactomedin-domain-containing glycoprotein, which regulates cell adhesion, proliferation, gastrointestinal inflammation, innate immunity and cancer metastasis. In the present study we investigated its role in skin regeneration. We found that OLFM4 expression is transiently upregulated in the proliferative phase of cutaneous wound healing in humans as well as in mice. Moreover, a significant increase in OLFM4 expression was detected in the skin of lesional psoriasis, a chronic inflammatory disease characterized by keratinocyte hyperproliferation. In vitro experiments demonstrated that OLFM4 selectively stimulated keratinocyte proliferation and increased both keratinocyte and fibroblast migration. Using proteotranscriptomic pathway analysis we revealed that transcription factors POU5F1/OCT4 and ESR1 acted as hubs for OLFM4-induced signalling in keratinocytes. In vivo experiments utilizing mouse splinted full-thickness cutaneous wound healing model showed that application of recombinant OLFM4 protein can significantly improve wound healing efficacy. Taken together, our results suggest that OLFM4 acts as a transiently upregulated inflammatory signal that promotes wound healing by regulating both dermal and epidermal cell compartments of the skin.
... Psoriasis is a chronic inflammatory skin disorder that is characterized by hyperproliferative skin lesions (Griffiths et al., 2021). As it is known that wounds heal faster in psoriatic skin (Morhenn et al., 2013), we analyzed THBS4 expression in psoriatic lesions (Figures 3A,B). We found that THBS4 was upregulated in psoriatic skin lesions by more than 2-fold ( Figure 3B). ...
Thrombospondin-4 (THBS4) is a non-structural extracellular matrix molecule associated with tissue regeneration and a variety of pathological processes characterized by increased cell proliferation and migration. However, the mechanisms of how THBS4 regulates cell behavior as well as the pathways contributing to its effects have remained largely unexplored. In the present study we investigated the role of THBS4 in skin regeneration both in vitro and in vivo. We found that THBS4 expression was upregulated in the dermal compartment of healing skin wounds in humans as well as in mice. Application of recombinant THBS4 protein promoted cutaneous wound healing in mice and selectively stimulated migration of primary fibroblasts as well as proliferation of keratinocytes in vitro. By using a combined proteotranscriptomic pathway analysis approach we discovered that β-catenin acted as a hub for THBS4-dependent cell signaling and likely plays a key role in promoting its downstream effects. Our results suggest that THBS4 is an important contributor to wound healing and its incorporation into novel wound healing therapies may be a promising strategy for treatment of cutaneous wounds.
... Overexpressed of vascular endothelial growth factor (VEGF) by both the keratinocytes and dermal fibroblasts and thereby accelerated rate of wound healing has been described in psoriasis. Cutaneous response to trauma may be unpredictable due to koebnerization [1]. The Koebner phenomenon describes the appearance of new isomorphic lesions in the spatially distinct traumatised previously uninvolved skin of a patient with pre-existing cutaneous disease [2,3]. ...
Background: Reconstruction of multiple facial lesions detected simultaneously pose more difficulties. Taking into the account on the importance of facial aesthetic subunits and possible requirement of future reconstructions, available options should be explored carefully. Case presentation: This report presents a case of multiple facial skin squamous cell carcinoma in a patient with lower eyelid ectropion from previous cheek advancement flap and underlying psoriasis. Lower eyelid was reconstructed with bipedicled Tripier flap from the upper lid. An analysis of the surgical options, reconstructions and the results observed during follow-up were discussed. Conclusion: Achieving surgical clearance with minimal tissue defect is the main goal in any oncologic resection. Skin laxity and local tissue quality should be considered in all reconstructions. In lower eyelid reconstruction, establish horizontal rather than vertical tension.
... Several studies have provided evidence that psoriasis demonstrates many characteristics of wound repair. Both lesional and non-lesional skin of individuals with psoriasis show significantly faster healing than skin of healthy individuals [60] . Hyperproliferation of keratinocytes, infiltration of inflammatory cells, and neovascularization are common processes both in wound repair and in psoriasis. ...
Current data suggest that tissue microenvironment control immune functions. Therefore, understanding the tissue environment in which immune activation occurs will enhance our capability to interfere with abnormal immune pathology. Here, we argue that studying the constitutively abnormal functions of clinically uninvolved psoriatic skin in patients with plaque type psoriasis is very important to better understand psoriasis pathobiology, because non‐lesional skin provides the tissue environment in which the psoriatic lesion develops. A key question in psoriasis is what initiates the abnormal, uncontrolled immune activation in the first place and the answer may lie in the skin. In light of this concept, we summarize abnormalities at the dermal‐epidermal junction region which shows a special “nonhealing‐like” micro‐wound phenotype in the psoriatic non‐lesional skin that may act as a crucial susceptibility factor in the development of the disease.
... However, a significant reduction in their density in the upper epidermis has been reported in skin diseases including psoriasis. Moreover, a decrease in the expression of NMDA receptors has been correlated with an increase in abnormal wound healing in psoriatic patients [114]. An increase in the skin wound healing process and Koebner reaction in the psoriatic patients suggest that the proliferation of keratinocytes is not inhibited appropriately. ...
... Using gene expression analysis, the greatest reduction in the expression of NMDA-R2C was found in TNF-α-exposed keratinocytes and the apparently increased proliferation of keratinocytes was attributed to the decrease in the expression of NMDA-R2C. Accordingly, it is suggested that the non-ability of psoriatic keratinocytes to increase the expression of NMDA-R2C in response to TNF-α may contribute in increasing the proliferation of keratinocytes observed in the process of Koebernization [114]. ...
... Along with it, the presence of alpha 2 beta 1 integrin in the suprabasal epidermal layers (normally it is in basal epidermal layer) [98,99]; increased expression of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis [26]; predominance of CD4 + cells over the CD8 + T cells in the epidermis [5]; increase in chemokines viz. CXCL8 and CCL20 [30], downregulation of mechanosensitive polycystin 1 protein [27], atypical chemokine receptor 2 (ACKR2) [28] and ionotropic NMDA receptors on the keratinocytes [114] also contribute in the development of secondary psoriatic lesions following skin injury. ...
Koebner phenomenon refers to the emergence of new psoriatic lesions in the healthy skin regions following an injury/trauma to psoriatic patients. The occurrence of psoriatic lesions at unusual areas of the body regions such as on penis, around eyes and on keloids suggests that the Koebner phenomenon may be responsible for these lesions. A number of agents/triggers have been reported to induce the development of new psoriatic lesions in healthy skin areas and these include, tattooing skin, radiations, skin incision, viral infections, and striae, etc. The different mechanisms that contribute in inducing the development of new psoriatic lesions as Koebernization include the involvement of mast cell-derived inflammatory mediators such as tryptase, IL-6, IL-8, Il-17 and IL-36γ. Moreover, an increased expression of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) also contribute in Koebernization. Apart from these, there is a critical role of alpha 2 beta1 integrins, S100A7 (psoriasin) and S100A15 (koebnerisin), change in the ratio of CD4+/CD8+ T cells, downregulation of mechanosensitive polycystin 1 protein, decrease in inflammation controlling atypical chemokine receptor 2 (ACKR2), reduced expression of N-methyl-d-aspartate (NMDA) receptors on the keratinocytes and increase in levels of chemokines (CXCL8 and CCL20) in inducing formation of new psoriatic lesions. The present review discusses about the role of Koebner phenomenon in the development of new psoriatic lesions. Moreover, it also describes the mechanisms involved in Koebernization in the form of discussion of different key targets that may be potentially modulated pharmacologically to attenuate/halt the development of new psoriatic lesions.
... Psoriatic plaques resemble the wound healing response with regard to many cellular and molecular mediators (41). Furthermore, the wound healing rate may be accelerated in both involved and uninvolved skin (49). Many genes activated during the wound healing process may be differentially involved either similarly or inversely in the molecular pathophysiology of psoriasis. ...
Joining main clinical manifestations of psoriatic skin disorder are inflammatory arthritis and nail lesions. Repetitive microdamage has been postulated as a main triggering factor in lesions of psoriatic arthritis. This concept of psoriatic disease might also be admissible for triggering nail lesions because the nail is a frequently traumatized structure. Here, we aimed to describe the conjectural injury mechanisms of nail complex with regard to acting biomechanical factors. Tissue repair response to physical microdamage may be altered in psoriatic disease. It is plausible to consider that a defective repair process in the dysregulated prepsoriatic tissue may lead to innate immune activation and further development of autoinflammatory lesions, although excessive inflammation is known to impair wound healing. Recently published data have revealed the importance of mechanosensitive Wingless‐type (Wnt) signaling in the pathophysiology of psoriasis and ankylosing spondylitis. The Wnt signaling system is involved in morphogenesis, repair, and regeneration as a biologic process main regulator. Wnt5a seems to be a dominating mediator in both psoriatic plaques and during the spondylitis process that might also be a linking molecule of psoriatic response to mechanical stress. Future studies should focus on complex responsive interactions of tissue repair regulators regarded in psoriatic disease.
... Disturbed expression of subunits of such receptors has been reported in the basal and apical part of the epidermis. 55,56 GABA and GABA A R expression has previously been found mainly in inflammatory cells in psoriasis. 57 Future therapies for alcohol and psoriasis might thus be targeted at neurotransmitter networks involved with both alcohol intake and the inflammatory processes. ...
Psoriasis is a chronic inflammatory skin disease that may be triggered or worsened by several factors, including alcohol. A higher than average alcohol consumption is common among individuals with psoriasis. Neurobiological signaling affected by alcohol intake includes a range of neurotransmitters, such as the dopaminergic, serotonergic, and tachykinergic systems, involved in reward and drug-seeking. These neurotransmitters may also have an impact on the inflammatory processes per se in psoriasis. Future therapy may, therefore, be targeted at neurotransmitter networks involved with both alcohol intake and the inflammatory processes.
... 58,59 In general, psoriasis does not appear to have a negative effect on wound healing. 60,61 However, the Koebner phenomenon may result in patients developing psoriatic lesions over surgery sites 62 and tattoos, 63 among other injuries. This phenomenon is more common in patients with unstable, undertreated disease. ...
General purpose:
To provide information about the diagnosis and management of cutaneous psoriasis.
Target audience:
This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.
Learning objectives/outcomes:
After completing this continuing education activity, the provider should be better able to: ABSTRACT: Psoriasis is a chronic inflammatory disease that is characterized by plaque, inverse, guttate, pustular, and erythrodermic variants. This review focuses on the epidemiology, diagnosis, and treatment of cutaneous psoriasis. Other related topics discussed include peristomal psoriasis, the Koebner phenomenon, and the relationship between biologic therapy and wound complications.
... On the basis of skin transcriptome data that are available for dolphins ( fig. 2), we propose that the classical suprabasal keratins have been replaced by K6 and K17 in cetaceans. This evolutionary switch in suprabasal keratins resembles the inducible change of the keratin expression in terrestrial mammalian skin during the epidermal regeneration response to wounding or during pathological epidermal hyperproliferation in psoriasis (Leigh et al. 1995;Navarro et al. 1995;McGowan and Coulombe 1998;Mazzalupo et al. 2003;Morhenn et al. 2013). The change from K1/K10 to K6/K17 is accompanied by thickening of the epidermis in terrestrial mammals and the thickness of the epidermis has also strongly increased in cetaceans (Sokolov 1982;Hicks et al. 1985; fig. ...
Keratins are the main intermediate filament proteins of epithelial cells. In keratinocytes of the mammalian epidermis they form a cytoskeleton that resists mechanical stress and thereby are essential for the function of the skin as a barrier against the environment. Here, we performed a comparative genomics study of epidermal keratin genes in terrestrial and fully aquatic mammals to determine adaptations of the epidermal keratin cytoskeleton to different environments. We show that keratins K5 and K14 of the innermost (basal), proliferation-competent layer of the epidermis are conserved in all mammals investigated. In contrast, K1 and K10, which form the main part of the cytoskeleton in the outer (suprabasal) layers of the epidermis of terrestrial mammals, have been lost in whales and dolphins (cetaceans) and in the manatee. Whereas in terrestrial mammalian epidermis K6 and K17 are expressed only upon stress-induced epidermal thickening, high levels of K6 and K17 are consistently present in dolphin skin, indicating constitutive expression and substitution of K1 and K10. K2 and K9, which are expressed in a body site-restricted manner in human and mouse suprabasal epidermis, have been lost not only in cetaceans and manatee but also in some terrestrial mammals. The evolution of alternative splicing of K10 and differentiation-dependent upregulation of K23 have increased the complexity of keratin expression in the epidermis of terrestrial mammals. Taken together, these results reveal evolutionary diversification of the epidermal cytoskeleton in mammals and suggest a complete replacement of the quantitatively predominant epidermal proteins of terrestrial mammals by originally stress-inducible keratins in cetaceans.
... Recently, Tsoi et al. (2015) profiled lncRNA expression in psoriasis skin, revealing LOC100130476 as top downregulated in lesional compared with nonlesional skin of psoriasis patients, which is a chronic inflammatory skin disease sharing some features with wounded skin, for example, epidermis thickening and inflammation (Morhenn et al., 2013;Nickoloff et al., 2006). Also, LOC100130476 was recently reported to be downregulated in esophageal squamous cell carcinoma (Guo et al., 2016a). ...
Chronic wounds represent a major and growing health and economic burden worldwide. A better understanding of molecular mechanisms of normal as well as impaired wound healing is needed to develop effective treatment. Herein we studied the potential role of long noncoding RNA LOC100130476 in skin wound repair. LOC100130476 is an RNA polymerase II–encoded polyadenylated transcript present in both cytoplasm and nucleus. We found that its expression was lower in wound-edge keratinocytes of human chronic wounds compared to normal wounds of healthy donors and intact skin. In cultured keratinocytes, LOC100130476 expression was induced by TGF-β signaling. By reducing LOC100130476 expression with antisense oligos or activating its transcription with CRISPR/Cas9 Synergistic Activation Mediator system, we showed that LOC100130476 restricted the production of inflammatory chemokines by keratinocytes, while enhancing cell migration. In line with this, knockdown of LOC100130476 impaired re-epithelization of human ex vivo wounds. Based on these results, we named LOC100130476 wound and keratinocyte migration–associated long noncoding RNA 2 (WAKMAR2). Moreover, we identified a molecular network that may mediate the biological function of WAKMAR2 in keratinocytes using microarray. In summary, our data suggest that WAKMAR2 is an important regulator of skin wound healing and its deficiency may contribute to the pathogenesis of chronic wounds.
