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Journal of the European Academy of... Mar 2022Germline autosomal dominant and autosomal recessive mutations in PERP, encoding p53 effector related to PMP-22 (PERP), a component of epidermal desmosomes, have been... (Review)
Review
BACKGROUND
Germline autosomal dominant and autosomal recessive mutations in PERP, encoding p53 effector related to PMP-22 (PERP), a component of epidermal desmosomes, have been associated with a spectrum of keratodermas. Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK). Biallelic recessive frameshift and missense mutations are associated with milder forms of the disease, including generalised erythrokeratoderma and PPK.
OBJECTIVES
To add new insights into the genotype-phenotype correlations as a consequence of PERP mutations and to provide a comprehensive review of the literature.
METHODS
Among 26 previously unresolved families within a cohort of 180 extended Iranian families with syndromic or non-syndromic ichthyosis, two families with shared clinical features were examined by whole-exome sequencing and genome-wide homozygosity mapping. Mycological and dermatopathological studies were performed to further characterise their atypical phenotypic presentations.
RESULTS
In two unrelated multiplex consanguineous families affected by ichthyosis, two novel biallelic PERP variants, NM_022121.5, c.89T > C, p.Leu30Pro and c.466G > C, p.Gly156Arg, located inside of genomic homozygosity regions of the probands were detected. Interestingly, some patients had areas of scaly psoriasiform plaques on the background of generalised ichthyosis that appeared during active cutaneous fungal infections. Mycological examinations of these lesions revealed infections caused by Candida albicans, Epidermophyton floccosum, or Trichophyton rubrum. Histopathology of the psoriasiform lesions shared some features with psoriasis, which when combined with clinical presentation, led to incorrect diagnosis of guttate psoriasis or pustular psoriasis.
CONCLUSIONS
PERP variants in ichthyosis patients can confer susceptibility to recalcitrant cutaneous fungal infections. Additionally, patients with episodic psoriasiform dermatitis in the setting of keratoderma should be considered for PERP genotyping and cutaneous fungal examinations.
Topics: Eczema; Genes, Tumor Suppressor; Humans; Ichthyosis; Iran; Membrane Proteins; Mutation; Mycoses; Pedigree
PubMed: 34863005
DOI: 10.1111/jdv.17856 -
The Journal of Pathology Oct 2023Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The...
Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin β1 subunit to form integrin α11β1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11 ) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11 and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11 mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Animals; Mice; Dermatitis; Disease Models, Animal; Imiquimod; Inflammation; Integrin alpha Chains; Psoriasis; Skin
PubMed: 37565309
DOI: 10.1002/path.6162 -
Dermatologic Therapy Dec 2022
Topics: Humans; Cisplatin; Psoriasis; Drug Eruptions; Exanthema
PubMed: 36219524
DOI: 10.1111/dth.15921 -
The Journal of Rheumatology Nov 2023Acute guttate psoriasis (AGP) is considered an uncommon variant of psoriasis (PsO), characterized as a widespread eruption of erythematous, psoriasiform papules, and...
Acute guttate psoriasis (AGP) is considered an uncommon variant of psoriasis (PsO), characterized as a widespread eruption of erythematous, psoriasiform papules, and plaques on the trunk, extremities, and scalp. Predisposing factors include a family history of PsO, variation in the main PsO susceptibility gene , and previous infection with viruses or acute β-hemolytic A program focused on controversies and recent advances in understanding AGP was presented at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 annual meeting. Topics included an overview of clinical presentation and natural history, predisposing genetic and environmental factors, and the recent molecular profiling that supports classification of AGP as a form of PsO. Early molecular profiling studies using proteomic signatures have suggested similarities between AGP and contact dermatitis, but recent studies using gene expression profiling and gene set enrichment scores demonstrate that AGP is more similar to chronic PsO. The expression of regulatory immune pathways seen with AGP suggests potential for early and sustained remission if the disease is suppressed by targeted treatments. Published case reports documenting clinical improvement of AGP with biologics that antagonize interleukin (IL)-12/23, IL-23, and IL-17 support the role of the IL-23/IL-17 axis in AGP, similar to that in PsO. Data supporting the use of antibiotics and other therapeutic agents for AGP are lacking, and randomized controlled trials are needed. Trial design for AGP is challenged by the low incidence, tendency for spontaneous remission, lack of validated end points, and the need for long-term follow up.
Topics: Humans; Interleukin-17; Proteomics; Psoriasis; Anti-Bacterial Agents; Exanthema; Interleukin-23; Arthritis, Psoriatic
PubMed: 37657796
DOI: 10.3899/jrheum.2023-0500 -
Theranostics 2024Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the...
Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the progression of psoriasiform dermatitis. However, how these two types of cells communicate remains obscure. We induced a mouse model with experimental psoriasiform dermatitis by Imiquimod (IMQ). To investigate whether damaged keratinocytes promote macrophage polarization and accelerate skin lesions by releasing extracellular vesicle (EV), purified EV were isolated from the primary epidermis of 5-day IMQ-induced psoriasiform dermatitis model mice, and then fluorescence-labeled the EV with PKH67. The EV was injected into the skin of mice treated with IMQ or vehicle 2 days . In addition, we established a co-culture system of the human monocytic cell line (THP-1) and HaCaT, and THP-1/HaCaT conditioned media culture model respectively. Subsequently, we evaluated the effect of Leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EV on macrophage activation. We demonstrated macrophages can significantly promote keratinocyte inflammation and macrophage polarization may be mediated by intercellular communication with keratinocytes. Interestingly, IMQ-induced 5-day, keratinocyte-derived EV recruited macrophage and enhanced the progression of skin lesions. Similar to results , EV released from M5-treated HaCaT significantly promotes Interleukin 1β (IL-1β) and Tumor necrosis factor α (TNF-α) expression of THP-1 cells. Importantly, we found that LRG1-enriched EV regulates macrophages via TGF beta Receptor 1 (TGFβR1) dependent process. Our findings indicated a novel mechanism for promoting psoriasiform dermatitis, which could be a potential therapeutic target.
Topics: Humans; Animals; Mice; Keratinocytes; Macrophages; Extracellular Vesicles; Glycoproteins; Inflammation; Dermatitis
PubMed: 38250043
DOI: 10.7150/thno.89180 -
Frontiers in Pharmacology 2022Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However,...
Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood. To investigate the function and mechanism of CB2R in PsD and itch in mice. Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells. We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4 T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins. Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.
PubMed: 35173615
DOI: 10.3389/fphar.2022.790712 -
The Journal of Dermatological Treatment Dec 2023Atopic dermatitis (AD), a chronic-relapsing inflammatory skin disorder, manifests with intense itching and eczematous lesions impairing quality of life. A heterogeneous... (Review)
Review
Atopic dermatitis (AD), a chronic-relapsing inflammatory skin disorder, manifests with intense itching and eczematous lesions impairing quality of life. A heterogeneous population, and regional clinical practices for treating AD warrant the development of guidelines in Qatar. Therefore, guidelines for the management of moderate-to-severe AD in Qatar have been developed and discussed. Experts, including dermatologists and immunologists, used the Delphi technique for developing guidelines. Consensus was defined as ≥75% agreement or disagreement. AD is highly prevalent in primary and tertiary dermatology centers. AD-associated foot eczema and psoriasiform eczema are more frequent in Qatar than in Europe or USA. SCORing Atopic Dermatitis Index quantifies disease severity and itch. Dermatology Life Quality Index assesses the quality of life. Atopic Dermatitis Control Tool assesses long-term disease control. Moderate-severe AD benefits from new topicals like Janus-kinase-inhibitors or PDE4-inhibitors combined with phototherapy. Currently approved systemic agents are dupilumab, baricitinib, abrocitinib, and upadacitinib. New anti-IL-13 and anti-IL-31 therapies will soon be available. Patient education, allergy testing, and comorbidity consideration are critical in the management of AD. The expert panel established a comprehensive and pragmatic approach to managing moderate-to-severe AD, thereby assisting clinical decision-making for healthcare professionals in Qatar.
Topics: Humans; Dermatitis, Atopic; Expert Testimony; Qatar; Quality of Life; Eczema; Pruritus
PubMed: 37700510
DOI: 10.1080/09546634.2023.2251622 -
Pediatric Dermatology Nov 2021Psoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform...
BACKGROUND/OBJECTIVES
Psoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform eruptions after initiation of dupilumab in children.
METHODS
Records of patients ≤18 years of age with atopic dermatitis who developed psoriasiform dermatitis during treatment with dupilumab were reviewed retrospectively.
RESULTS
Six children, 4-18 years of age, on dupilumab for severe atopic dermatitis developed new-onset psoriasiform dermatitis at a median duration of 8 months (range, 6-12 months) after dupilumab initiation. Typical locations of psoriasis were involved (face, scalp, trunk, and extensor extremities). The majority showed clearance or near clearance with the use of medium-strength to potent topical corticosteroid ointments and 83% continued use of the dupilumab. A 7th patient had psoriasis, in addition to severe atopic dermatitis, and the psoriasis was unmasked by its failure to respond to dupilumab.
CONCLUSION
Although unusual, psoriasiform lesions can appear during effective treatment with dupilumab for atopic dermatitis, potentially reflecting a shift toward cutaneous IL-23/T 17 pathway activation with dupilumab-induced suppression of type 2 immunity.
Topics: Adult; Antibodies, Monoclonal, Humanized; Child; Dermatitis, Atopic; Eczema; Humans; Retrospective Studies
PubMed: 34647354
DOI: 10.1111/pde.14820 -
Life (Basel, Switzerland) Dec 2022Isorhamnetin (IRh), which has a wide range of pharmacological effects, is one of the most significant active components in the fruits of L. and the leaves of L. It...
Isorhamnetin (IRh), which has a wide range of pharmacological effects, is one of the most significant active components in the fruits of L. and the leaves of L. It protects the heart and brain, in addition to possessing anti-tumor, anti-inflammatory, antioxidant, organ protection, and anti-obesity properties. We sought to assess IRh's anti-psoriatic activity, explore its immunomodulatory properties in reducing the severity of psoriatic symptoms, and evaluate its potential immunotherapeutic effects. We used IRh to treat imiquimod (IMQ)-induced psoriasis in BALB/C mice and examined the underlying mechanisms. The outcomes demonstrated that IRh reduced epidermal hyperplasia, lowered PASI scores, and improved histopathological psoriasiform lesions in IMQ-induced mice. IRh attenuated the accumulation of malondialdehyde (MDA), and also reversed the reduction caused by IMQ of superoxide dismutase (SOD) and catalase (CAT) in skin tissues. Additionally, IRh effectively inhibited IMQ's ability to increase proinflammatory cytokines such as TNF-α, IL-6, IL-17A, and transcription factor NF-κB. Furthermore, IRh significantly reduced the percentage of Th1 and Th17 in the spleens of mice treated with IMQ and suppressed the maturation of splenic dendritic cells. Overall, our research suggests that IRh protects against oxidative stress and inflammation in the pathogenesis of psoriasis, with potential for the development of new and potent medication for the treatment of psoriasis.
PubMed: 36556472
DOI: 10.3390/life12122107 -
British Journal of Pharmacology Aug 2023Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6)...
BACKGROUND AND PURPOSE
Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis.
EXPERIMENTAL APPROACH
The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms.
KEY RESULTS
This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation.
CONCLUSIONS AND IMPLICATIONS
This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.
Topics: Humans; Animals; Mice; Proto-Oncogene Proteins c-akt; Imiquimod; Phosphatidylinositol 3-Kinases; Psoriasis; Inflammation; Dermatitis; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 36967633
DOI: 10.1111/bph.16080