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Frontiers in Medicine 2022Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, and dupilumab, a human monoclonal antibody, is the firstly approved biological drug for AD....
Case report: Clinical and histopathological characteristics of psoriasiform erythema and IL-17A cytokines expression on lesioned skin in atopic dermatitis children treated with dupilumab.
BACKGROUND
Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, and dupilumab, a human monoclonal antibody, is the firstly approved biological drug for AD. Psoriasiform erythema (PE) during dupilumab treatment in adults has been reported. This study describes the risk of PE in children after initiation of dupilumab treatment.
OBJECTIVES
To evaluate the cytokines gene expression in the transition of atopic dermatitis symptoms to psoriasiform erythema during dupilumab treatment in children.
METHODS
Two 17-year-old teenage twin patients with AD were included in this study who developed psoriasiform erythema after initiation of dupilumab. The lesional skin biopsy specimens were obtained for the histopathological investigation and RNA Fluorescence Hybridization (RNA-FISH). Dermoscopy, cytometry (cytokine detection in the blood), and blood investigations were completed for the pedigree and the lesioned descriptions.
RESULTS
Two twin patients with AD presented with erythematic scaly plaques on the back, scalp, abdomen, and extensor extremities after 20 weeks of dupilumab treatment. The transitional change of AD to psoriasiform erythema treated with dupilumab was observed. Our subjects' dermoscopy showed pinpoint bleeding and white scales on pink background. Histopathology features showed psoriasiform hyperplasia, epidermal hyperplasia (acanthosis), ectatic capillaries, perivascular lymphocytes infiltration, and parakeratosis, with the absence of the granular cell layer. mRNA (RNA-FISH) cytokines gene expression showed a significantly high concentration of IL-17A. Blood investigation results showed a high concentration of (Immunoglobulin E) IgE and Eosinophils, and cytokines detection in blood showed IL-5,6 and IL-17 in one patient; however, only IL-5 in another patient. The dupilumab was discontinued and initiated with Baricitinib. Baricitinib showed a significant reduction in skin lesions.
CONCLUSION
Psoriasiform erythema can appear during dupilumab treatment in atopic dermatitis children. Potently, by suppressing skewed Th2 activation in patients with AD, the balance might shift toward Th1/Th17 predominance, and psoriasis develops. Baricitinib is a potential drug for psoriasiform erythema with significant therapeutic effects.
PubMed: 35966849
DOI: 10.3389/fmed.2022.932766 -
The Journal of Investigative Dermatology Jan 2023The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in...
The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 in vitro and in vivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-κB pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.
Topics: Animals; Humans; Mice; Eczema; Inflammation; Keratinocytes; Lysine; Phosphatidylinositol 3-Kinases; Psoriasis; RNA, Long Noncoding; DNA-Binding Proteins
PubMed: 35870559
DOI: 10.1016/j.jid.2022.06.025 -
Frontiers in Pharmacology 2022: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%-1.99% of the world's population. Our aim was...
: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%-1.99% of the world's population. Our aim was to identify novel potential therapeutic strategies for psoriasis. : Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for and functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis. : WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation . Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation. : We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response ERK1/2 and STAT3 dependent signaling pathways in psoriasis.
PubMed: 35860030
DOI: 10.3389/fphar.2022.850967 -
The Journal of Investigative Dermatology Dec 2022Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory...
Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14Il9ra mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14Il9ra mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14Il9ra mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14Il9ra epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.
Topics: Animals; Mice; Dermatitis; Disease Models, Animal; Imiquimod; Inflammation; Interleukin-9; Keratinocytes; Peptide YY; Psoriasis; Skin
PubMed: 35850207
DOI: 10.1016/j.jid.2022.06.021 -
Journal of Lower Genital Tract Disease Jul 2022The aim of the study was to evaluate clinicopathologic features of cases demonstrating an acanthotic tissue reaction not clearly consistent with psoriasis, lichen...
OBJECTIVE
The aim of the study was to evaluate clinicopathologic features of cases demonstrating an acanthotic tissue reaction not clearly consistent with psoriasis, lichen simplex chronicus, mycosis, or condyloma.
MATERIALS AND METHODS
This is a retrospective pathologic case series of biopsies reported as "benign acanthotic lesion" and "acanthotic tissue reaction" that lacked a clear diagnosis on expert review. Cases with nuclear atypia were excluded. Clinical and histopathologic data were collected, immunohistochemistry for p16 and p53 were obtained, and molecular testing for 28 common anogenital human papillomavirus (HPV) genotypes was undertaken.
RESULTS
There were 17 cases with a median age of 47 years. Unilaterality and medial location were clinical reasons for diagnostic difficulty. Histopathologic uncertainty often related to lack of papillary dermal fibrosis to support lichen simplex chronicus or psoriasiform lesions without parakeratosis, subcorneal pustules, and/or mycotic elements. Firm pathologic diagnoses were not possible, but 3 groups emerged: favoring chronic dermatitis, favoring psoriasis, and unusual morphologies. p16 results were negative or nonblock positive while p53 was normal or basal overexpressed. Human papillomavirus testing was negative in 12, low positive for HPV 16 in 1, unassessable in 3, and not requested in 1.
CONCLUSIONS
There is a group of acanthotic tissue reactions that cannot be classified with standard histopathologic assessment. Further clinicopathologic research into unilateral acanthotic lesions may provide insight into separation of psoriasis and mycosis when organisms are absent. Once nuclear atypia is excluded, immunohistochemistry for p16 and p53 and HPV molecular testing do not assist in diagnostic identification.
Topics: Alphapapillomavirus; Female; Humans; Middle Aged; Neurodermatitis; Papillomaviridae; Papillomavirus Infections; Psoriasis; Retrospective Studies; Tumor Suppressor Protein p53; Vulvar Neoplasms
PubMed: 35543596
DOI: 10.1097/LGT.0000000000000681 -
Cellular and Molecular Life Sciences :... Apr 2022Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral...
Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.
Topics: Animals; Dermatitis; Epidermis; Keratinocytes; Mice; Nerve Fibers; Psoriasis
PubMed: 35488965
DOI: 10.1007/s00018-022-04299-x -
International Journal of Molecular... Apr 2022Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the...
Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the current study, imiquimod-induced psoriasiform dermatitis was used for monitoring the changes in skin thickness, transepidermal water loss, body weight, blood perfusion and drug permeability for a topical cream formulation of caffeine, both in wild type and in knock out mice. Morphological characterization of control and diseased tissues was performed by scanning electron microscopy and two-photon microscopy. The chemically induced psoriatic group showed increased skin permeability for the model drug during disease progression. In wild type and TRPA1 KO mice, however, enhanced skin thickness and hyperkeratosis blocked further increase of drug penetration at the late phase (96 h). These results indicate that topical drug therapy can be more effective in early phases of plaque development, when skin thickness is lower. Although paracellular connections (tight junctions) are looser in the advanced phase, hyperkeratosis blocks drug delivery through the transappendageal routes. Novel drug formulations may have the potency for effective drug delivery across the epidermal barrier even in the advanced phase. For development of more effective topical drugs, further research is proposed to explore drug penetration both in healthy and diseased conditions.
Topics: Animals; Disease Models, Animal; Epidermis; Lab-On-A-Chip Devices; Mice; Optical Imaging; Permeability; Psoriasis; Skin
PubMed: 35457056
DOI: 10.3390/ijms23084237 -
Indian Journal of Dermatology 2021
PubMed: 35283530
DOI: 10.4103/ijd.ijd_1100_20 -
Pharmaceutics Feb 2022Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated...
Cutaneous Delivery of Cosmeceutical Peptides Enhanced by Picosecond- and Nanosecond-Domain Nd:YAG Lasers with Quick Recovery of the Skin Barrier Function: Comparison with Microsecond-Domain Ablative Lasers.
Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium-aluminum-garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional ablative CO and fully ablative erbium (Er):YAG lasers were also used for comparison. In the Franz diffusion cell study, pig or mouse skin was treated with a laser before exposure to palmitoyl tripeptide (PT)-1, PT-38, and copper tripeptide (CT)-1 at a concentration of 150 μM. Psoriasiform, atopic dermatitis (AD)-like, and photoaged skins were also developed as permeation barriers. The non-ablative laser elicited the ultrastructural disruption of the stratum corneum and epidermal vacuolation. All laser modalities significantly increased the skin permeation of peptides in vitro. The non-ablative laser chiefly enhanced peptide delivery to the receptor compartment, whereas the ablative laser mainly increased the intracutaneous peptide deposition. The picosecond- and nanosecond-domain Nd:YAG lasers elevated the amount of PT-1 in the receptor up to 40- and 22-fold compared with untreated skin, respectively. Laser treatment promoted peptide delivery in barrier-deficient and inflamed skins, although this enhancement effect was less than that observed in healthy skin. Fluorescence microscopy indicated the capability of the non-ablative laser to deliver peptides to deeper skin strata. The ablative laser confined the peptide distribution in the epidermis. Confocal microscopy showed that peptides penetrated the skin along the microdots created by the fractional Nd:YAG and CO lasers. The skin barrier function determined by transepidermal water loss suggested quick recovery when using a nanosecond-domain laser (within 4 h). A longer period was needed for the skin treated with the fully ablative Er:YAG laser (76-84 h). Nanosecond non-ablative laser-facilitated peptide delivery may become an efficient and safe approach for cosmeceutical applications.
PubMed: 35214181
DOI: 10.3390/pharmaceutics14020450 -
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