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 Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

2018 ◽  
Author(s):  
Jieqiong Qu ◽  
Sabine Tanis ◽  
Jos P.H. Smits ◽  
Evelyn N. Kouwenhoven ◽  
Martin Oti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Epidermal Cell ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Epidermal Keratinocytes ◽  
Cell Identity ◽  
Keratinocyte Proliferation ◽  
Eec Syndrome ◽  
Proliferation And Differentiation

AbstractTranscription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In humans mutations in p63 cause several developmental disorders with defects of ectoderm-derived structures including the epidermis. The underlying molecular mechanisms of these mutations however remain unclear. Here we characterized the transcriptome and epigenome from EEC syndrome patients carrying mutations in the p63 DNA-binding domain. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed that the deregulated gene expression in p63 mutant keratinocytes resulted from an altered enhancer landscape contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers in mutant keratinocytes were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression as well as the enhancer distribution. Our findings support the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes and identify a novel mechanism whereby p63 DNA-binding mutations associated with EEC syndrome rewire the enhancer landscape and affect epidermal cell identity.

Defined System to Assess the in Vitro Induction of a Psoriasis Phenotype on Normal Keratinocytes by Fibroblasts from Psoriatic Subjects

1997 ◽  
Vol 2 (1) ◽  
pp. 20-25 ◽  
Author(s):  
Gerald G. Krueger ◽  
Cynthia M. Jorgensen
Keyword(s):  
Normal Subjects ◽  
Psoriatic Skin ◽  
Keratinocyte Proliferation ◽  
Normal Keratinocytes ◽  
Proliferation And Differentiation ◽  
Soluble Mediator ◽  
Epidermal Proliferation ◽  
Cellular Components ◽  
Proliferation In Vitro

Background: Research has shown that involved as well as uninvolved skin of psoriatic subjects have an inherent defect that manifests, at a minimum, as nonapparent epidermal hyperplasia. Fibroblasts have been shown to regulate epidermal proliferation and differentiation; furthermore, fibroblasts from patients with psoriasis have altered growth, response, and mediator release when compared with normal. Objective: We conjectured that it might be possible to generate the enhanced epidermal proliferation inherent to psoriatic skin in vitro using a defined interactive culture system with cellular components from the skin of normal and psoriatic subjects. Methods: To reduce the variables whereby fibroblasts stimulate keratinocyte proliferation in vitro, a system was developed that does not permit direct contact between keratinocytes and fibroblasts, but does permit the exchange of media and mediators as well as an assessment of keratinocyte growth as a function of time. Fibroblasts from involved and uninvolved sites from biopsies of seven untreated psoriatic subjects were assessed for their effect on the growth of keratinocytes from normal subjects. Results: Analysis shows that five of seven fibroblast sources from involved sites and six of seven from uninvolved sites of psoriatic subjects induce normal keratinocytes to display enhanced outgrowth. Three of 14 fibroblast sources consistently do not induce this change. Fibroblasts from uninvolved sources are particularly effective, with a mean of 40 ± 8% (SD) more growth than with normal fibroblasts. Conclusion: It is concluded that fibroblasts from psoriatics can induce the phenotype of increased epidermal proliferation on normal keratinocytes via a soluble mediator in a defined system.

scholarly journals IL-6 Negatively Regulates IL-22Rα Expression on Epidermal Keratinocytes: Implications for Irritant Contact Dermatitis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Benjamin Frempah ◽  
Lerin R. Luckett-Chastain ◽  
Randle M. Gallucci
Keyword(s):  
Contact Dermatitis ◽  
Inflammatory Response ◽  
Protein Expression ◽  
Inflammatory Cytokine ◽  
Epidermal Keratinocytes ◽  
Irritant Contact Dermatitis ◽  
Cytokine Release ◽  
Epidermal Hyperplasia ◽  
Keratinocyte Proliferation ◽  
Proliferation And Differentiation

Irritant Contact Dermatitis (ICD) is characterized by epidermal hyperplasia and inflammatory cytokine release. IL-6 has been shown to be involved in the pathogenesis of ICD; however, the involvement of the IL-22/IL-22Rα axis and its relation to IL-6 in the inflammatory response following irritant exposure are unknown. Using a chemical model of ICD, it was observed that mice with a keratinocyte-specific knockout of IL-6Rα (IL-6RαΔker) presented with increased inflammation and IL-22Rα and IL-22 protein expression relative to WT following irritant exposure, indicating that IL-6Rα deficiency in epidermal keratinocytes leads to the upregulation of IL-22Rα and its ligand during ICD. Furthermore, it was shown that IL-6 negatively regulates the expression of IL-22Rα on epidermal keratinocytes. This effect is functional as the effects of IL-22 on keratinocyte proliferation and differentiation were markedly reduced when keratinocytes were pretreated with IL-6 prior to IL-22 treatment. These results show that IL-6 modulates the IL-22/IL-22Rα axis in the skin and suggest that this occurrence may be associated with the increased epidermal hyperplasia and exacerbated inflammatory response observed in IL-6RαΔker mice during ICD.

Anti-proliferative effects of an herbal formulated cream on human keratinocytes and its implication for psoriasis treatment

2016 ◽  
Vol 5 (07) ◽  
pp. 4686 ◽  
Author(s):  
Harsha M. R.* ◽  
Baidyanath Mishra ◽  
Chaithra C. S. ◽  
Vivekananda Ramana
Keyword(s):  
Cell Model ◽  
Test Material ◽  
Epidermal Keratinocytes ◽  
Recurrence Rates ◽  
Inflammatory Infiltration ◽  
Keratinocyte Proliferation ◽  
Psoriasis Treatment ◽  
Study Material ◽  
Keratinocyte Cell ◽  
Promising Source

Psoriasis is a chronic inflammatory skin disorder which affects more than 3% of the population worldwide and is characterized histopathologically by proliferative imbalance and abnormal differentiation of epidermal keratinocytes and inflammatory infiltration. Hence, loss of regulation in keratinocyte proliferation and differentiation makes it a typical pathophysiological phenomenon in psoriasis manifestation. Traditionally, herbal products used in treating psoriasis have shown promising effects in several clinical studies with relatively fewer adverse effects, higher remission and lower recurrence rates. In our previous study, the polyherbal formulation of InnoVision’s test material was found to induce AQP-3 expression in keratinocyte cell line. In the present study, we screened the study material for its anti-proliferative properties using cultured human HACAT keratinocyte cell model. Our experimental results suggest that InnoVision’s Psoriderm Cream is a promising source which can be effectively used as an herb-based topical agent for psoriasis treatment. Evidence is provided that inhibition of keratinocyte proliferation and improving skin hydration via induction of aquaporin-3 stimulation is the possible underlying mechanism for the observed anti-psoriatic action of study material. 

scholarly journals A Rose Extract Protects the Skin against Stress Mediators: A Potential Role of Olfactory Receptors

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4743
Author(s):  
Romain Duroux ◽  
Anne Mandeau ◽  
Gaelle Guiraudie-Capraz ◽  
Yannick Quesnel ◽  
Estelle Loing
Keyword(s):  
Physiological Role ◽  
Olfactory Receptors ◽  
Major Constituent ◽  
Epidermal Keratinocytes ◽  
Functional Assay ◽  
Skin Explants ◽  
Stress Mediators ◽  
Double Blinded ◽  
Split Face

Olfactory receptors (ORs) are expressed and active in various human tissues, including the skin. Although the sense of smell plays an important physiological role in the regulation of mood and stress, a link between olfactive compounds, ORs, and skin stress has yet to be established. This study aims to investigate the role of newly identified skin ORs and agonists in the modulation of skin stress. Screening for odorant molecules was done with cAMP functional assay to identify OR agonists. RT-qPCR and immunofluorescence microscopy were conducted to identify and quantify ORs in epidermal keratinocytes (NHEKs) and human skin explants, as well as to evaluate specific markers (G6PDH, loricrin, and γH2AX) of stress-induced skin alterations. A randomized double-blinded, split-face clinical study was performed on a panel of stressed women to measure the benefits of OR agonist treatment for skin. Three new ORs (OR10A6, OR2AG2, and OR11H4) were identified in skin. A specific Rose extract and its major constituent (phenylethyl alcohol) were found to activate these ORs. The extract composition was revealed by both GC/FID and GC/MS analyses simultaneously and showed the presence of 34 volatiles molecules. Moreover, epinephrine induces a skin stress response characterized by increased expression of G6PD, loricrin, and γH2AX biomarkers, and a decrease of OR expression. These effects were prevented in the presence of rose extract and its benefits were confirmed clinically by a decrease in the appearance of under-eye dark circles. Altogether, our findings suggest that ORs may represent a new, promising way to treat stress-associated skin disorders.

scholarly journals Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis

2021 ◽  
Vol 10 (17) ◽  
pp. 3822
Author(s):  
Trung T. Vu ◽  
Hanako Koguchi-Yoshioka ◽  
Rei Watanabe
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Inflammatory Diseases ◽  
Adaptive Immune Response ◽  
Psoriatic Skin ◽  
Peripheral Tissues ◽  
Potential Index ◽  
Circulating T Cells ◽  
Chronic Skin ◽  
Resident Memory T Cells

Tissue-resident memory T cells (TRM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although TRM originate from circulating T cells, TRM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin TRM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8+ TRM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin TRM are available to date, psoriatic skin TRM are affected in the current treatments of psoriasis. Targeting skin TRM or using TRM as a potential index for disease severity can be an attractive strategy in psoriasis.

Sign in / Sign up

Export Citation Format

Share Document