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Biological & Pharmaceutical Bulletin Oct 2023Psoriasis is classically regarded as a T-helper 1 (Th1) response-dominant disease believed to be antagonized by the Th2 response, which is responsible for allergic...
Psoriasis is classically regarded as a T-helper 1 (Th1) response-dominant disease believed to be antagonized by the Th2 response, which is responsible for allergic diseases, such as atopic dermatitis. The roles of these responses in psoriasis and the relationship between psoriasis and atopic dermatitis have received increasing attention because it is estimated that more than one million patients are concomitantly affected by psoriasis and atopic dermatitis. To address this, we attempted to determine the characteristics of imiquimod-induced psoriasiform lesions in mice with a concomitant allergic response after co-application of the unrelated allergen ovalbumin onto the skin. Imiquimod cream containing ovalbumin was successively applied to the right back skin of hairless HR female mice. Psoriasiform scores were determined for 11 d, and then, the resected skin thickness, spleen weight, and serum antibody levels were examined. In some experiments, mice were allowed free access to ovalbumin-containing water for 10 d before skin application to induce oral tolerance. Imiquimod cream induced psoriasis, and its severity increased upon simultaneous ovalbumin treatment. Increases in anti-ovalbumin immunoglobulin G2a (IgG2a) levels, a Th1 response indicator, and IgG1 and IgE levels, Th2 response indicators, were mediated by ovalbumin addition. Oral tolerance against ovalbumin effectively decreased ovalbumin-exacerbated imiquimod-induced psoriasis, in parallel with a decrease in levels of anti-ovalbumin antibodies. These results suggest that the concomitant allergic response induced by ovalbumin application exacerbates imiquimod-induced psoriasis. This implies that allergic responses to unrelated allergens might exacerbate psoriasis in humans and that modulating such responses could be an effective new approach to treat psoriasis.
PubMed: 37599076
DOI: 10.1248/bpb.b23-00353 -
Clinical, Cosmetic and Investigational... 2023As a mediator of inflammation resolution, lipoxin A4 (LXA4) mainly plays an anti-inflammatory role and promotes inflammation resolution. LXA4 plays an inhibiting...
INTRODUCTION
As a mediator of inflammation resolution, lipoxin A4 (LXA4) mainly plays an anti-inflammatory role and promotes inflammation resolution. LXA4 plays an inhibiting inflammatory role in a variety of diseases, tissues and cells, including keratinocytes. Psoriasis is a chronic inflammatory skin disease mediated by dysregulation of inflammation of immune cells and keratinocytes. However, the expression and role of LXA4 in psoriasis-like mouse models are still unclear.
METHODS
Imiquimod (IMQ) topical treatment of dorsal skin induces psoriasis-like dermatitis in BALB/c mice, pretreated intraperitoneally with or without LXA4 prior to IMQ application. Severity of dorsal lesions is assessed by using a modified human scoring system and histopathology. The concentration of LXA4 and the expression of ALOX15 (a key gene in LXA4 metabolic synthesis) in lesional skins were detected by ELISA and Western blot. Quantitative PCR and ELISA were conducted to detect the mRNA and secretion levels of inflammatory cytokines. The proportion of IL-17A-producing γδT cells in skin and skin draining cervical lymph nodes and helper (Th) 17 cells in spleens was evaluated by flow cytometry. Western blotting was used to analyze the expressions of p-STAT3 and TRAF6.
RESULTS
The concentration of LXA4 and the expression of ALOX15 were decreased in IMQ-induced lesional skin. LXA4 significantly relieved psoriasis-like lesions in IMQ-induced mouse models. Furthermore, LXA4 decreased IMQ-induced systemic inflammation, including reduced the proportion of IL-17A-producing gdT cells in skin and skin draining cervical lymph nodes and Th17 cells in spleens, the secretion and expression of CCL20, IL-17A, IL-1β, and TNF-α in skin and serum. LXA4 markedly inhibited IMQ-induced expression of TRAF6 and p-STAT3.
CONCLUSION
LXA4 significantly ameliorates IMQ-induced psoriasis-like inflammation, and LXA4 can be used as a target for psoriasis treatment.
PubMed: 37575152
DOI: 10.2147/CCID.S418467 -
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 -
JAAD Case Reports Sep 2023
PubMed: 37560139
DOI: 10.1016/j.jdcr.2023.06.020 -
Immunity, Inflammation and Disease Jul 2023A recent study confirmed that thiolutin (THL), as a potent inflammasome inhibitor, plays a promising therapeutic role in multiple inflammatory disease models. However,...
INTRODUCTION
A recent study confirmed that thiolutin (THL), as a potent inflammasome inhibitor, plays a promising therapeutic role in multiple inflammatory disease models. However, the effect of THL on psoriasis has not been reported so far.
METHODS
A psoriasiform dermatitis model was prepared by applying 5% imiquimod (IMQ) cream on mice. A total of 36 mice were randomly divided into six groups: control, model, model + THL-L/M/H (THL, 1/2.5/5 mg/kg/day), model + methotrexate (1 mg/kg/day). Psoriasis area and severity index (PASI) scores were observed and calculated. The histological changes in skin, liver, and kidney tissues were observed by hematoxylin and eosin staining. Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and blood creatinine were measured by automatic biochemistry analyzer. The size of the spleens was determined, and the proportion of Foxp3 + CD4+ regulatory T (Treg) cells in the spleens was tested by flow cytometry. The proinflammatory factors and nucleotide oligomerization domain nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome protein levels were examined by reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunohistochemistry, respectively.
RESULTS
THL administration preeminently reduced the thickness, scaling, and erythema of the skin lesions, alleviated IMQ-induced psoriasiform lesions in mice, reduced the PASI score, and ameliorated histopathological changes in mouse skin. The spleen index was decreased by almost half and the proportion of Foxp3 + CD4+ Treg cells was increased after intervention by THL. THL intervention did not affect liver and kidney function, but decreased the expression levels of proinflammatory factors and NLRP3 inflammasome in the skin of psoriatic mice.
CONCLUSIONS
THL may alleviate IMQ-induced psoriasis-like manifestations in mice by inhibiting NLRP3 inflammasome.
Topics: Mice; Animals; Imiquimod; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Psoriasis; Dermatitis; Inflammation; Forkhead Transcription Factors
PubMed: 37506136
DOI: 10.1002/iid3.877 -
PeerJ 2023Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal...
BACKGROUND
Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal transducers and activators of transcription 3 (STAT3) play a crucial role in linking activated keratinocytes and immunocytes during psoriasis development. T helper (Th) 17 cells and secreted interleukin (IL)-17A contribute to its pathogenesis. IL-17A treated STAT3 overexpressing mouse model might serve as an animal model for psoriasis.
METHODS
In this study, we established a mouse model of psoriasiform dermatitis by intradermal IL-17A injection in STAT3 overexpressing mice. Transcriptome analyses were performed on the skin of wild type (WT), STAT3, and IL-17A treated STAT3 mice. Bioinformatics-based functional enrichment analysis was conducted to predict biological pathways. Meanwhile, the morphological and pathological features of skin lesions were observed, and the DEGs were verified by qPCR.
RESULTS
IL-17A treated STAT3 mice skin lesions displayed the pathological features of hyperkeratosis and parakeratosis. The DEGs between IL-17A treated STAT3 mice and WT mice were highly consistent with those observed in psoriasis patients, including S100A8, S100A9, Sprr2, and LCE. Gene ontology (GO) analysis of the core DEGs revealed a robust immune response, chemotaxis, and cornified envelope, et al. The major KEGG enrichment pathways included IL-17 and Toll-like receptor signaling pathways.
CONCLUSION
IL-17A exacerbates psoriasis dermatitis in a STAT3 overexpressing mouse.
Topics: Mice; Animals; Interleukin-17; Imiquimod; Psoriasis; Skin; Disease Models, Animal; Dermatitis
PubMed: 37465147
DOI: 10.7717/peerj.15727 -
The Journal of Dermatology Oct 2023Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an...
Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)-23-induced mouse model of psoriasiform dermatitis. Both in situ hybridization and bulk RNA sequencing showed PLD2 gene expression is significantly higher in lesional relative to non-lesional skin of psoriasis patients or the skin of healthy subjects. PLD2 expression is also enriched in residual lesions from patients on biologic therapies. Murine in vivo studies showed that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears, as reflected by decreases in ear thickness, expression of defensin beta 4A and the S100 calcium binding protein A7A, macrophage infiltrate, and expression of CXCL10 and IL-6. However, the expression of type 17 cytokines, IL-17A and IL-17F, were not reduced. Dual knockout of PLD1 and PLD2 offered little additional protection compared to PLD2 knockout alone in the IL-23 model. In addition, pharmacological inhibition with a pan-PLD1/PLD2 inhibitor also suppressed IL-23-induced psoriasiform dermatitis. Bone-marrow-derived macrophages from wild type (WT) and PLD2 knockout (KO) mice exhibited little difference in viability and sensitivity to lipopolysaccharide and/or interferon gamma, or resiquimod (R848). PLD2 deficiency did not alter the differentiation and function of Th17 cells in an ex vivo study with splenocytes isolated from WT and PLD2 KO mice. Overall, these data suggest that PLD2 may play a role in the pathophysiology of psoriasis. Reducing macrophage infiltrate and cytokine/chemokine production might contribute to an anti-inflammatory effect observed in PLD2 knockout mice. Further studies are required to better understand the mechanisms by which PLD2 contributes to skin lesions in psoriasis patients and psoriasiform dermatitis models.
PubMed: 37455419
DOI: 10.1111/1346-8138.16899 -
Actas Dermo-sifiliograficas Jan 2024Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been... (Review)
Review
BACKGROUND
Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions.
MATERIAL AND METHODS
Retrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain.
RESULTS
We collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution.
CONCLUSIONS
Paradoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases.
Topics: Humans; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor Inhibitors; Adalimumab; Infliximab; Psoriasis; Immunologic Factors; Necrosis
PubMed: 37437689
DOI: 10.1016/j.ad.2023.06.016 -
Clinical, Cosmetic and Investigational... 2023Pretibial pruritic papular dermatitis (PPPD) is a distinctive skin disorder in response to persistent pretibial manipulation. Clinically, it manifests as multiple...
Pretibial pruritic papular dermatitis (PPPD) is a distinctive skin disorder in response to persistent pretibial manipulation. Clinically, it manifests as multiple discrete, pruritic, flesh-colored-to-erythematous papules and plaques confined to the pretibial area. The histological hallmark of PPPD comprises irregular epidermal psoriasiform hyperplasia with parakeratosis and spongiosis, dermal fibrosis, and lymphohistiocytic infiltration. Due to its rarity and underrecognition, the prevalence and standard treatment of the disease have yet to be well elucidated. Here, we present a case of PPPD in a 60-year-old female presenting with numerous pruritic, erythematous-to-brownish papules and plaques on bilateral pretibial areas for 1.5 years. The lesions were significantly improved after 1 month of additional treatment with oral pentoxifylline. In this report, we aim to raise awareness in recognizing PPPD since it manifests unique clinical, dermoscopic, and histological features, representing pretibial skin's response to chronic rubbing. In addition, we proposed a novel effective therapy for the disease using pentoxifylline.
PubMed: 37366429
DOI: 10.2147/CCID.S420726 -
Journal of Ethnopharmacology Dec 2023Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for...
Liangxue Jiedu formula improves imiquimod-induced psoriasiform dermatitis with circadian desynchrony by regulating Th17 cell differentiation based on network pharmacological analysis.
ETHNOPHARMACOLOGICAL RELEVANCE
Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades.
AIM OF THE STUDY
This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies.
MATERIALS AND METHODS
The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting.
RESULTS
We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression.
CONCLUSION
LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.
Topics: Animals; Mice; Interleukin-17; Imiquimod; Skin; Psoriasis; Cell Differentiation; Dermatitis; Disease Models, Animal; Th17 Cells; Mice, Inbred BALB C
PubMed: 37331449
DOI: 10.1016/j.jep.2023.116807