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The Journal of Investigative Dermatology May 2022Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent...
Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent studies suggest that BAs regulate T helper 17 cell function, but the underlying mechanism of this action and their therapeutic value in disease models remains unclear. Using an IL-23 minicircle DNA-based murine model of psoriasiform dermatitis, we showed that oral administration of secondary BAs, including lithocholic acid (LCA), deoxycholic acid, and 3-oxoLCA, significantly improved psoriasiform dermatitis without inducing apparent hepatotoxicity. Of the BAs tested, LCA possessed the greatest potency in treating psoriasiform dermatitis. Intravenous administration of LCA at a much lower dosage (compared with oral treatment) showed a comparable antipsoriatic effect and markedly suppressed the IL-17A response. Ex vivo experiments revealed that LCA reduced IL-17A production in IL-23-stimulated murine T cells in the absence of BA receptors TGR5 or FXR. Strikingly, BAs inhibited CCL20 expression in keratinocytes, which led to reduced migration of CCR6-expressing Jurkat cells cultured in the conditioned medium of stimulated keratinocytes. Thus, BAs improve psoriasiform dermatitis with minimal toxicity via direct inhibition of IL-17A production and blockade of CCL20-mediated trafficking, supporting the potential use of BAs in psoriasis.
Topics: Animals; Bile Acids and Salts; Chemokine CCL20; Eczema; Humans; Interleukin-17; Interleukin-23; Mice; Psoriasis; Receptors, CCR6
PubMed: 34808237
DOI: 10.1016/j.jid.2021.10.027 -
Journal of the European Academy of... May 2024Psoriasis is an inflammatory skin disease. The pathogenesis of psoriasis has not been fully elucidated. T-lymphokine-activated killer cell-originated protein kinase...
BACKGROUND
Psoriasis is an inflammatory skin disease. The pathogenesis of psoriasis has not been fully elucidated. T-lymphokine-activated killer cell-originated protein kinase (TOPK) activity increases in a proinflammatory environment, and inhibiting TOPK blocks inflammation. However, whether TOPK is involved in the pathogenesis of psoriasis remains to be identified.
OBJECTIVES
We aimed to study the role of TOPK in psoriasis and attempted to find a drug targeting TOPK for the prevention and treatment of psoriasis.
METHOD
Firstly, the expressions of TOPK in psoriatic patients, psoriatic cell and animal model were analysed by Gene Expression Omnibus database, immunohistochemistry (IHC) staining and western blot (WB). After inhibiting TOPK by chemical or gene knockout, the effect of TOPK on the development of psoriasis was verified in cell and animal model by WB, qRT-PCR, ELISA, haematoxylin-eosin (H&E) and IHC staining. Moreover, phosphoproteomic analysis was performed to explore the signalling pathways regulated by TOPK in the occurrence and development of psoriasis. Then, an in vitro kinase assay was performed to prove TOPK kinase activity was inhibited by worenine. Ultimately, WB, qRT-PCR, ELISA, H&E and IHC staining were used to verify the anti-psoriasis effect of worenine by inhibiting TOPK was in cell and animal model.
RESULTS
In this study, we found that TOPK was highly expressed in psoriasis patients, psoriatic cell and animal model, which suggests that TOPK might be associated with psoriasis pathogenesis. Interestingly, chemical or genetic inhibition of TOPK alleviated M5- and imiquimod (IMQ)-induced psoriasis-like dermatitis, which further confirmed the role of TOPK in promoting the development of psoriasis. Moreover, we determined that worenine inhibited TOPK kinase activity. In addition, worenine relieved M5- and IMQ-induced psoriasiform dermatitis by inhibiting TOPK activity.
CONCLUSIONS
T-lymphokine-activated killer cell-originated protein kinase promotes the development of psoriasis. Therefore, TOPK might be a promising drug target for the prevention and treatment of psoriasis. Worenine alleviates psoriasiform dermatitis by inhibiting TOPK activity, providing new strategies for clinical intervention.
Topics: Psoriasis; Humans; Animals; Mice; Disease Models, Animal; Signal Transduction; Mitogen-Activated Protein Kinase Kinases
PubMed: 38131517
DOI: 10.1111/jdv.19724 -
International Immunopharmacology Mar 2024To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice.
OBJECTIVE
To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice.
METHODS
An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3) and wild-type (Ptx3) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization.
RESULT
The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3 mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3 mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups.
CONCLUSIONS
This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.
Topics: Animals; Mice; C-Reactive Protein; Cyclooxygenase 2; Dermatitis; Disease Models, Animal; Imiquimod; Interleukin-6; Macrophages; Psoriasis; Serum Amyloid P-Component; Tumor Necrosis Factor-alpha; Humans; Disease Progression; Mice, Knockout; Mice, Inbred C57BL
PubMed: 38457930
DOI: 10.1016/j.intimp.2024.111805 -
Proceedings of the National Academy of... Dec 2023Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over...
Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.
Topics: Humans; Animals; Melanoma; Psoriasis; Inflammation; Protein Sorting Signals; Dermatitis; RNA, Messenger; Disease Models, Animal
PubMed: 38109533
DOI: 10.1073/pnas.2313009120 -
The Journal of Allergy and Clinical... May 2024The introduction of immune checkpoint inhibitors (ICIs) has transformed the management of various malignancies. Alongside their therapeutic success, the widespread... (Review)
Review
The introduction of immune checkpoint inhibitors (ICIs) has transformed the management of various malignancies. Alongside their therapeutic success, the widespread application of ICIs has unveiled a spectrum of immune-related adverse events (irAEs), most often affecting the skin. Cutaneous irAEs (cirAEs) encompass a range from common morbilliform and lichenoid rashes to more severe conditions such as bullous dermatoses and psoriasiform eruptions, each presenting distinct clinical challenges. Moreover, less common but clinically severe cutaneous reactions like toxic epidermal necrolysis have also been observed. cirAEs are frequently observed, with an incidence ranging from 37% to 70% for anti-cytotoxic T lymphocyte-associated antigen-4 antibodies and 17% to 40% for anti- programmed death-1/anti-programmed death ligand-1 antibodies. Recognizing the critical need for effective therapeutic strategies, this review carefully examines current approaches and guidelines for managing cirAEs.
Topics: Humans; Immune Checkpoint Inhibitors; Drug Eruptions; Neoplasms; Skin; Stevens-Johnson Syndrome
PubMed: 38548170
DOI: 10.1016/j.jaip.2024.03.034 -
Giornale Italiano Di Dermatologia E... Apr 2020Treatment with antihypertensive drugs may be associated with different dermatological adverse reactions.
INTRODUCTION
Treatment with antihypertensive drugs may be associated with different dermatological adverse reactions.
EVIDENCE ACQUISITION
We systematically reviewed the literature available on the MEDLINE (PubMED) databases, up to July 2018. We searched for the terms "calcium-channel blockers" or "angiotensin-converting enzyme inhibitors" or "angiotensin II receptors blockers" or "diuretics" or "beta blockers" AND "dermatological effects" or "skin disease."
EVIDENCE SYNTHESIS
The most important cutaneous events occurring during treatment with calcium-channel blockers are represented by pedal edema and photosensitivity with consequent increased risk of skin cancer. Moreover, other adverse reactions are eczematous and psoriasiform dermatitis, subacute cutaneous lupus erythematosus, and rarely toxic epidermal necrolysis. In patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptors blockers, angioedema, psoriasis and pemphigus can be exacerbated. Furthermore, some authors associated the use of these medications with the onset of skin neoplasms. As for diuretics, the most relevant cutaneous reactions are represented by subacute cutaneous lupus erythematosus and leukocytoclastic vasculitis. Photosensitivity is another important event related to diuretics use. Eventually, itching is often related to the use of thiazides, particularly in elderly patients. With regards to beta blockers, we should remember a significant association with psoriasis, lichen planus, subacute cutaneous lupus erythematosus, and an increased risk of skin cancer.
CONCLUSIONS
During antihypertensive treatment, several dermatological reactions may occur. Clinicians should inform their patients of the increased risk of cutaneous lesions associated with the use of these drugs, and perform periodic examination of the skin.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Eruptions; Humans
PubMed: 31195782
DOI: 10.23736/S0392-0488.19.06360-0 -
Pharmaceuticals (Basel, Switzerland) Nov 2023: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is...
: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. : Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords "ustekinumab" or "Stelara" in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. : Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. : Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings.
PubMed: 38004414
DOI: 10.3390/ph16111548 -
Archive of Clinical Cases 2019Psoriasiform dermatoses represent a wide spectrum of inflammatory conditions, with several major forms represented by psoriasis, as the prototype of this category,... (Review)
Review
Psoriasiform dermatoses represent a wide spectrum of inflammatory conditions, with several major forms represented by psoriasis, as the prototype of this category, followed by pustular psoriasis, Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus and large-plaques parapsoriasis. They create a diagnostic challenge, both clinical and histopathological, because of their complexity and frequent overlapping of the microscopical features. The characteristic histopathological features of psoriasiform reaction comprise extensive hyperkeratosis, with horizontally confluent but vertically intermittent parakeratosis, which alternate with orthokeratosis, thin granular layer, with relative frequent mitoses, uniform elongated and fused rete ridges, edematous superficial papillary dermis, with dilated capillaries, perivascular lymphocytic infiltrate, Munro's microabscesses, and spongiform pustules of Kogoj. Our paper aims to review the histopathology of major form of psoriasiform dermatoses and to emphasize the characteristic microscopical differences between them, for a better approach of the diagnosis as an important key for clinical and therapeutical management. Using the clinicopathological correlations, a thoroughly evaluation of the microscopical features and compartments distribution or special stainings and techniques, the range of differential diagnosis can be decreased and a more accurate diagnostic can be usually achieved. The insights into the pathogenic mechanisms can lead to new therapeutic opportunities targeted to the specific type of inflammatory lesion.
PubMed: 34754910
DOI: 10.22551/2019.24.0603.10155 -
BioMedicine Dec 2019Psoriasis is the prime example of psoriasiform tissue pattern and should be differentiated from other psoriasiform dermatoses both clinically and histopathologically.
BACKGROUND
Psoriasis is the prime example of psoriasiform tissue pattern and should be differentiated from other psoriasiform dermatoses both clinically and histopathologically.
AIM
To evaluate immunohistochemical expression of P53, Ki-67, and CD34 in psoriasis and psoriasiform dermatitis for diagnostic purposes.
METHODS
An analytical cross-sectional study was performed on the paraffin blocks of 60 psoriasis and 31 psoriasiform dermatitis patients between 2014 and 2017. The selected formalin-fixed paraffin-embedded tissues from each biopsy specimen were cut into 4-micron sections. Initial sections were stained by hematoxylin and eosin staining. Primary antihuman antibodies against P53, Ki-67, and CD34 were applied. Positive control samples for biomarkers were received from former strongly positive samples of papillary endothelial hyperplasia, high grade lymphoma, and breast ductal carcinoma for CD34, Ki-67, and P53, respectively.
RESULTS
Out of 60 psoriasis patients, 56.7% were men, with the mean age of 36.8 years. From 31 psoriasiform patients, 45.2% were men, with the mean age of 37.5 years. Both groups were matched in terms of sex and age. The mean staining of three markers was more significant in psoriasiform dermatitis than psoriasis.
CONCLUSION
In spite of some other researches, the present study showed expression of P53, Ki-67, and CD34 biomarkers were significantly higher in psoriasiform dermatitis than psoriasis.
PubMed: 31724940
DOI: 10.1051/bmdcn/2019090426 -
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