scholarly journals Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

2018 ◽  
Author(s):  
Suhyeon Kim ◽  
Seoyoon Bae ◽  
Jihyun Park ◽  
Geun-Hyoung Ha ◽  
Kyungrim Hwang ◽  
...  
Keyword(s):  
Skin Inflammation ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Intercellular Signaling ◽  
Multisystem Disease ◽  
Signaling Mechanism ◽  
Inflammatory Microenvironment ◽  
Systemic Signaling ◽  
Ubiquitin E3 Ligase ◽  
Chronic Skin

AbstractChronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

scholarly journals Changes in Proteome of Fibroblasts Isolated from Psoriatic Skin Lesions

2020 ◽  
Vol 21 (15) ◽  
pp. 5363
Author(s):  
Agnieszka Gęgotek ◽  
Pedro Domingues ◽  
Adam Wroński ◽  
Elżbieta Skrzydlewska
Keyword(s):  
Signal Transduction ◽  
Skin Lesions ◽  
Dermal Fibroblasts ◽  
Metabolic Effects ◽  
Psoriatic Skin ◽  
Proteomic Profile ◽  
Intercellular Signaling ◽  
Antioxidant Proteins ◽  
Skin Epidermis ◽  
Proinflammatory Factors

The dermal fibroblasts are in constant contact with the cells of the immune system and skin epidermis. Therefore, they are essential for the development of lesions in psoriasis. The aim of this study was to assess the changes in the proteomic profile of fibroblasts in the dermis of psoriasis patients, and to discuss the most significant changes and their potential consequences. The proteomic results indicate that fibroblast dysfunction arises from the upregulation of proinflammatory factors and antioxidant proteins, as well as those involved in signal transduction and participating in proteolytic processes. Moreover, downregulated proteins in psoriatic fibroblasts are mainly responsible for the transcription/translation processes, glycolysis/ adenosine triphosphate synthesis and structural molecules. These changes can directly affect intercellular signaling and promote the hyperproliferation of epidermal cells. A better understanding of the metabolic effects of the proteomic changes observed could guide the development of new pharmacotherapies for psoriasis.

Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice

2018 ◽  
Vol 9 (2) ◽  
pp. 299-309 ◽  
Author(s):  
S. Holowacz ◽  
C. Blondeau ◽  
I. Guinobert ◽  
A. Guilbot ◽  
S. Hidalgo ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Oral Treatment ◽  
Lactobacillus Rhamnosus ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Skin Lesions ◽  
Lactobacillus Salivarius ◽  
Tnf Α ◽  
Microscopic Evaluation ◽  
Chronic Skin

Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13-acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1β, IL-6, tumour necrosis factor alpha (TNF-α), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1×109 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that their use could be beneficial in dermatological conditions such as AD.

scholarly journals Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy

2021 ◽  
Vol 22 (8) ◽  
pp. 3968
Author(s):  
Hye Ran Kim ◽  
Jin Cheol Kim ◽  
Seok Young Kang ◽  
Hye One Kim ◽  
Chun Wook Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Related Factor ◽  
Related Factors ◽  
Tetrachlorodibenzo P Dioxin

Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.

scholarly journals Overexpression of Cd40 Ligand in Murine Epidermis Results in Chronic Skin Inflammation and Systemic Autoimmunity

2001 ◽  
Vol 194 (5) ◽  
pp. 615-628 ◽  
Author(s):  
Annette Mehling ◽  
Karin Loser ◽  
Georg Varga ◽  
Dieter Metze ◽  
Thomas A. Luger ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Skin Inflammation ◽  
Cd40 Ligand ◽  
Skin Lesions ◽  
Systemic Autoimmunity ◽  
Immune Mediated ◽  
In Situ Activation ◽  
Chronic Skin ◽  
Antigen Presenting

CD40–CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell–deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.

Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1048-1057 ◽  
Author(s):  
Rainer Kunstfeld ◽  
Satoshi Hirakawa ◽  
Young-Kwon Hong ◽  
Vivien Schacht ◽  
Bernhard Lange-Asschenfeldt ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Transgenic Mice ◽  
Lymphatic Vessel ◽  
Inflammatory Diseases ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Epidermal Differentiation ◽  
Delayed Type Hypersensitivity ◽  
Psoriatic Skin ◽  
Vegf Receptor

Abstract Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy.

scholarly journals TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Nima Etemadi ◽  
Michael Chopin ◽  
Holly Anderton ◽  
Maria C Tanzer ◽  
James A Rickard ◽  
...  
Keyword(s):  
E3 Ligase ◽  
Adaptive Immune System ◽  
Sphingosine Kinase ◽  
Skin Inflammation ◽  
Psoriatic Skin ◽  
Sphingosine Kinase 1 ◽  
Ubiquitin E3 Ligase ◽  
Tnf Superfamily ◽  
Sphingosine 1 Phosphate

TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.

scholarly journals Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1338
Author(s):  
Savannah D. Neu ◽  
Anna Strzepa ◽  
Dustin Martin ◽  
Mary G. Sorci-Thomas ◽  
Kirkwood A. Pritchard, Jr. ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Plaque Psoriasis ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Autoimmune Response ◽  
Psoriatic Skin ◽  
Imiquimod Cream ◽  
Current Therapies ◽  
Study Support

Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions. To assess skin inflammation severity, an innovative mouse psoriasis scoring system was developed. We found that myeloperoxidase inhibition ameliorated psoriasis severity when administered either systemically or topically. The findings of this study support the role of oxidative damage in plaque psoriasis pathology and present potential new therapeutic avenues for further exploration.

Chronic Skin Lesions in Type 2 Diabetic Subjects

2018 ◽  
Vol 18 ◽  
Author(s):  
Eleonora Margherita Chisari ◽  
Borzi Antonio Maria ◽  
Luca Salvatore ◽  
Chisari Giuseppe ◽  
Chisari Clara Grazia
Keyword(s):  
Skin Lesions ◽  
Chronic Skin ◽  
Type 2 Diabetic

scholarly journals The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Chenliang Gou ◽  
Wenkai Ni ◽  
Panpan Ma ◽  
Fengbo Zhao ◽  
Zhou Wang ◽  
...  
Keyword(s):  
Physiological Role ◽  
Neutrophil Infiltration ◽  
Proper Function ◽  
Psoriatic Skin ◽  
Epidermal Keratinocytes ◽  
Keratinocyte Proliferation ◽  
Proliferation And Differentiation ◽  
Long Time ◽  
Chronic Skin ◽  
Upregulated Genes

AbstractPsoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.

scholarly journals Sequestosome 1/p62 enhances chronic skin inflammation

2021 ◽  
Author(s):  
Supawadee Sukseree ◽  
Latifa Bakiri ◽  
Marta Palomo Irigoyen ◽  
Özge Uluçkan ◽  
Peter Petzelbauer ◽  
...  
Keyword(s):  
Skin Inflammation ◽  
Sequestosome 1 ◽  
Chronic Skin
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