Psoriasiform Dermatitis Research Articles

Phenotypic changes of lymphocyte populations in psoriasiform dermatitis animal model.

Psoriasis is a T cell mediated, chronic inflammatory autoimmune skin disease that affects up to 2–3% of the global population and leads to a decrease in quality of life. Experimental data accumulated in recent years highlighted the important role played by the immune system in the pathogenesis of this disease. Non-human psoriasis models are an important research tool that attempts to reproduce the clinical features of the disease in order to explain the pathogenesis of psoriasis and to identify possible therapeutic targets. Imiquimod-based murine model of psoriatic dermatitis is an alternative to traditional models of experimental psoriasis in mice and the induced dermatitis closely mimics the pathologic changes in human psoriasis. In order to emphasize changes in immune cell populations involved in lesion pathogenesis, we performed a murine model of psoriasiform dermatitis model by topical IMQ application. The progress and the severity of IMQ-induced skin inflammation were clinically (PASI score) and histopathologically evaluated. The immunological changes induced by IMQ treatment in lymphocyte populations from peripheral blood and spleen were evaluated by flow cytometry. The main changes observed in peripheral blood were the significantly increased T-CD8a+ lymphocyte and NK1.1+ cell percentages and the decreased T-CD4+ and B lymphocyte percentages in IMQ-treated mice. In spleen samples, lymphocytes showed the same tendency of variation as in peripheral blood, but without statistical significance. A significant decrease of B cells percentages was observed in spleen suspensions. Data obtained in skin samples may suggest the involvement of CD3ε+, CD4+ and CD8a+ cells in the lesional process. This murine model was analyzed by performing a basic cellular profile at three levels: peripheral blood, spleen and skin. The evaluation aimed to establish the immune framework of this experimental model that could further be used for etipathogenic mechanism identification and/or for studies regarding targeted therapies.

Chemerin/ChemR23 axis triggers an inflammatory response in keratinocytes through ROS-sirt1-NF-κB signaling.

Psoriasis is a chronic disease which carries the emotional and social burden, promotes joint disability and raises comorbidity possibility in patients. Obesity is closely correlated with the occurrence of psoriasis and adipokines produced by adipose tissues were found to be critical culprits. Chemerin is one of them and its expression was increased in patients with psoriatic arthritis. In our hypothesis, chemerin might act on keratinocytes and promote an inflammatory response, which plays an essential role in psoriatic epidermis. To validate our hypothesis, HaCaT cells and primary human keratinocytes were treated with chemerin (5, 10, and 20 ng/mL for 24 hours). Enzyme-linked immunosorbent assay (ELISA) was used to determine the secretion of inflammatory factors. Nuclear factor-κB (NF-κB) activation and p65 acetylation were evaluated by Western blot analysis. The expression and activity of sirtuin 1 (sirt1), a deacetylase act on p65, were also analyzed. The results showed that chemerin prompted inflammatory factors secretion, NF-κB activation and p65 acetylation through chemerin receptor 23 receptor. Chemerin constrained the expression and deacetylase activity of sirt1 through augment of reactive oxygen species (ROS) production. Additionally, chemerin exacerbated psoriasiform dermatitis in imiquimod-treated mice model. In conclusion, chemerin can seduce inflammatory response and promote NF-κB activation through inhibition of sirt1 activity by ROS production.

Lesional upregulation of SLURP1 immunostaining parallels disease severity in psoriasis vulgaris patients.

The exact pathogenesis of psoriasis is still unclear. SLURP1 is vital for the normal differentiation of keratinocytes, and could therefore be involved in psoriasis. In this study we investigated the immunohistochemical staining reaction of SLURP1 in psoriasis vulgaris patients and its possible relation to disease pathogenesis. 20 patients with psoriasis vulgaris, 20 patients with psoriasiform dermatitis and 20 normal skin samples were studied. Psoriasis severity was measured with a combination of PASI and DLQI scores. Lesional and non-lesional sites were biopsied for each psoriasis patient. A single biopsy sample was taken for cases with psoriasiform dermatitis and for controls. All sections were immunostained for SLURP1 according to the manufacturer's protocol. Significant differences were noted in SLURP1 immunostaining between lesional and non-lesional biopsies of psoriasis patients and between lesional biopsies of psoriasis patients and lesional sites of psoriasiform dermatitis. However, the differences between non-lesional biopsies of psoriasis patients and normal controls were not significant. Furthermore, the grading of SLURP1 immunostaining paralleled the degree of psoriasis severity. SLURP1 immunostaining is significantly increased in lesional skin of psoriasis vulgaris and not in psoriasiform dermatitis, which demonstrates the role of SLURP1 in the pathogenesis of psoriasis. SLURP1 could be used as a biological marker for psoriasis severity, and this hypothesis warrants further investigation.

5-hydroxytryptophan attenuates imiquimod-induced psoriasiform dermatitis probably through inhibition of IL-17A production and keratinocyte activation.

Psoriasis is a chronic autoimmune disease with keratinocyte activation and lymphocyte infiltration in the skin. Our previous study found that 5-hydroxytryptophan (5(OH)Trp), a tryptophan metabolite, alleviated collagen-induced arthritis and suppressed cytokine production. In this study, we evaluated the effects of 5(OH)Trp in a mouse model for psoriasiform dermatitis, induced by imiquimod (IMQ). We showed that 5(OH)Trp significantly reduced the cumulative scores, epidermal thickness and ki-67 expression in the skin. In addition, 5(OH)Trp decreased local and systemic inflammation. Moreover, 5(OH)Trp significantly inhibited keratinocyte activation with decrease in IL-6 production and p-Erk1/2 and p-STAT3 expression. 5(OH)Trp also inhibited the differentiation of IFN-γ- and IL-17A-expressing CD4+ T cells and related cytokine production (TNF-α, IL-6, IL-17A and IFN-γ) in splenocytes. In conclusion, 5(OH)Trp can inhibit imiquimod-induced psoriasiform dermatitis in mice and inhibit activation in keratinocytes and splenocytes.

Macrophage Migration Inhibitory Factor (MIF) Drives Murine Psoriasiform Dermatitis.

The immunomodulator Macrophage Migration Inhibitory Factor (MIF) exerts pleiotropic immunomodulatory activities and has been implicated in the pathogenesis of diverse inflammatory diseases. Expression levels of MIF are also significantly elevated in the skin and serum of psoriasis patients, but the pathogenic significance of MIF in psoriasis is unknown. We have therefore addressed the role of MIF in two mouse models of psoriasis, namely in the imiquimod-induced psoriasiform dermatitis (IIPD) and the IL-23-induced dermatitis model. Daily treatment with Aldara™ cream, containing imiquimod, markedly increased the abundance of MIF in the skin and generated a cellular skin expression pattern of MIF closely resembling that in human plaque psoriasis. Deficiency in MIF significantly alleviated IIPD. On the clinical level, all hallmarks of psoriasiform dermatitis, including erythema, skin infiltration, and desquamation were reduced in Mif−/− mice. On the histopathological level, MIF deficiency decreased keratinocyte hyperproliferation, inflammatory cell infiltration, specifically with respect to monocyte-derived cells, and dermal angiogenesis, suggesting that MIF may be involved in the pathogenesis of psoriasiform dermatitis through several mechanisms. Similarly, MIF deficiency also significantly reduced disease in the IL-23-induced dermatitis model, suggesting that MIF is involved in the pathogenic pathways activated by IL-23 and required to achieve full-blown psoriasiform dermatitis. Collectively, our results lend support to a possible disease-promoting role of MIF in psoriasis, which should be further investigated.

A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice

There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4feeble except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.

Syndecan-1 Regulates Psoriasiform Dermatitis by Controlling Homeostasis of IL-17-Producing γδ T Cells.

IL-17 is a potent proinflammatory cytokine that drives pathogenesis of multiple autoimmune diseases, including psoriasis. A major source of pathogenic IL-17 is a subset of γδ T cells (Tγδ17) that acquires the ability to produce IL-17 while developing in the thymus. The mechanisms that regulate homeostasis of Tγδ17 cells and their roles in psoriasis, however, are not fully understood. In this paper, we show that the heparan sulfate proteoglycan syndecan-1 (sdc1) plays a critical role in regulating homeostasis of Tγδ17 cells and modulating psoriasis-like skin inflammation in mice. sdc1 was predominantly expressed by Tγδ17 cells (but not IL-17- Tγδ cells) in the thymus, lymph nodes, and dermis. sdc1 deficiency significantly and selectively increased the frequency and absolute numbers of Tγδ17 cells by mechanisms that included increased proliferation and decreased apoptosis. Adoptive transfer experiments ruled out a significant role of sdc1 expressed on nonhematopoietic cells in halting expansion and proliferation of sdc1-deficient Tγδ17 cells. When subjected to imiquimod-induced psoriasiform dermatitis, Tγδ17 cells in sdc1KO mice displayed heightened responses accompanied by significantly increased skin inflammation than their wild-type counterparts. Furthermore, transferred sdc1-deficient γδ T cells caused more severe psoriasiform dermatitis than their sdc1-sufficient counterparts in TCR-βδ KO hosts. The results uncover a novel role for sdc1 in controlling homeostasis of Tγδ17 cells and moderating host responses to psoriasis-like inflammation.

Is CCR6 Required for the Development of Psoriasiform Dermatitis in Mice?

Is CCR6 Required for the Development of Psoriasiform Dermatitis in Mice?

LB1563 Protective role of TRPA1 on imiquimod-induced psoriasiform dermatitis

LB1563 Protective role of TRPA1 on imiquimod-induced psoriasiform dermatitis

LB1561 Localized Aldara-induced psoriasiform dermatitis model using Finn chambers

LB1561 Localized Aldara-induced psoriasiform dermatitis model using Finn chambers

Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

BackgroundAnimal models of Psoriasis (PsO) are important for our understanding of the pathophysiology of human disease but rarely manifest all features of the disease. In order to facilitate greater understanding of the underlying biology of PsO it is key that we understand the strengths and limitations of models used. ObjectiveWhile humanized mouse models are available for PsO they remain technically challenging, expensive, require prolonged timelines and require a continued source of human tissue. Another approach is to focus on developing mechanistic models which recapitulate key features of human PsO. The role of the IL-23/IL-17 pathway as a key driver of human PsO is both well characterized and clinically validated. The goal of this manuscript is to provide a comprehensive disease and pharmacological assessment of IL-23 driven skin inflammation and its similarity to human psoriatic skin. MethodsIntradermal injection of IL-23 has been used to study the IL-23 pathway in rodents, and this current study further characterizes pathology, cellular infiltrate, and gene signature kinetics, as well as the modulation of disease features by clinically relevant agents. ResultsOur results indicate that IL-23 triggers an early and robust activation of the immune system resulting in accumulation of T cell and monocyte/macrophage populations. It also supports changes in gene expression that parallel those observed in human PsO samples and is responsive to biologics commonly used to treat PsO in the clinic. ConclusionsCollectively, our studies indicate that a 5 day model of IL-23 psoriasiform dermatitis can be used to assess the pharmacology of novel small molecules/biologics in the treatment of PsO.

Retrospective Chart Review of Cutaneous Adverse Events Associated with Tremelimumab in 17 Patients.

Tremelimumab is a monoclonal human antibody that inhibits cytotoxic T-lymphocyte-associated antigen 4, giving rise to increased T cell activation and interleukin-2 release. While this activation of the immune system provides a mechanism to recognize and destroy cancer cells, it also leads to off-target immune-related adverse events. Ipilimumab is a US Food and Drug Administration-approved anti-cytotoxic T-lymphocyte-associated antigen 4 antibody, which has a high incidence of cutaneous adverse events. While cutaneous adverse events for ipilimumab have been extensively studied, there is a distinct lack of cutaneous adverse event data for tremelimumab. We conducted a retrospective chart review of our institution's electronic medical records from January 2000 to March 2018 to characterize cutaneous adverse events induced by tremelimumab. Previous descriptions of tremelimumab cutaneous adverse events are limited to rash and pruritus. We found 17 patients treated with tremelimumab who had cutaneous adverse events including pruritus (12/17), eczematous dermatitis (8/17), morbilliform rash (5/17), vitiligo (2/17), xerosis (3/17), acneiform rash (2/17), and psoriasiform dermatitis (1/17). This case series demonstrates that cutaneous adverse events seen in patients taking tremelimumab overlap with those of ipilimumab. While there are some differences between rash characterizations of the two drugs, such as time to onset and clearance, the sample size of this case series is too small to draw any definite conclusions. This study addresses a gap in the descriptive knowledge on tremelimumab cutaneous adverse events and highlights the need for further large cohort prospective studies. Awareness of expected cutaneous toxicities and how best to treat these can help patients continue on immunotherapy regimens without delays or interruptions and give patients the best quality of life while receiving treatment.

IL-36α from Skin-Resident Cells Plays an Important Role in the Pathogenesis of Imiquimod-Induced Psoriasiform Dermatitis by Forming a Local Autoamplification Loop.

IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36β), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1β, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1β, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.

Chitosan-based nanoformulated (-)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis.

BackgroundPsoriasis is a chronic and currently incurable inflammatory skin disease characterized by hyperproliferation, aberrant differentiation, and inflammation, leading to disrupted skin barrier function. The use of natural agents that can abrogate these effects could be useful for the treatment of psoriasis. Earlier studies have shown that treatment of keratinocytes and mouse skin with the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) mitigated inflammation and increased the expression of caspase-14 while promoting epidermal differentiation and cornification. However, bioavailability issues have restricted the development of EGCG for the treatment of psoriasis.Materials and methodsTo overcome these limitations, we employed a chitosan-based polymeric nanoparticle formulation of EGCG (CHI-EGCG-NPs, hereafter termed nanoEGCG) suitable for topical delivery for treating psoriasis. We investigated and compared the efficacy of nanoEGCG versus native or free EGCG in vitro and in an in vivo imiquimod (IMQ)-induced murine psoriasis-like dermatitis model. The in vivo relevance and efficacy of nanoEGCG formulation (48 µg/mouse) were assessed in an IMQ-induced mouse psoriasis-like skin lesion model compared to free EGCG (1 mg/mouse).ResultsLike free EGCG, nanoEGCG treatment induced differentiation, and decreased proliferation and inflammatory responses in cultured keratinocytes, but with a 4-fold dose advantage. Topically applied nanoEGCG elicited a significant (p<0.01) amelioration of psoriasiform pathological markers in IMQ-induced mouse skin lesions, including reductions in ear and skin thickness, erythema and scales, proliferation (Ki-67), infiltratory immune cells (mast cells, neutrophils, macrophages, and CD4+ T cells), and angiogenesis (CD31). We also observed increases in the protein expression of caspase-14, early (keratin-10) and late (filaggrin and loricrin) markers of differentiation, and the activator protein-1 factor (JunB). Importantly, a significant modulation of several psoriasis-related inflammatory cytokines and chemokines was observed compared to the high dose of free EGCG (p<0.05). Taken together, topically applied nanoEGCG displayed a >20-fold dose advantage over free EGCG.ConclusionBased on these observations, our nanoEGCG formulation represents a promising drug-delivery strategy for treating psoriasis and possibly other inflammatory skin diseases.

Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation.

Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.

Eczematous reactions mimicking psoriasiform dermatitis induced by nivolumab for advanced lung cancer

Eczematous reactions mimicking psoriasiform dermatitis induced by nivolumab for advanced lung cancer

Extracellular ATP and IL-23 Form a Local Inflammatory Circuit Leading to the Development of a Neutrophil-Dependent Psoriasiform Dermatitis

Psoriasis is a chronic inflammatory skin disease dependent on the IL-23/IL-17 axis, a potent inflammatory pathway involved in pathogen clearance and autoimmunity. Several triggers have been proposed as initiators for psoriasis, including alarmins such as adenosine triphosphate. However, the role of alarmins in psoriasis pathogenesis and cutaneous inflammation has not been well addressed. Studies show that signaling through the P2X7 receptor (P2X7R) pathway underlies the development of psoriasiform inflammation. In this regard, psoriasiform dermatitis induced by IL-23 is dependent on P2X7R signaling. Furthermore, direct activation of the P2X7R is sufficient to induce a well-characterized psoriasiform dermatitis. Mechanistic studies determined that P2X7R-induced inflammation is largely dependent on the IL-1β/NLRP3 inflammasome pathway and neutrophils. In conclusion, this work provides basic mechanistic insight into local inflammatory circuits induced after purinergic P2X7R signaling that are likely involved in the pathogenesis of many inflammatory diseases, such as psoriasis.

The respective contributions of P2X7 receptor variants to the development of psoriasiform dermatitis

Abstract Psoriasis is a chronic inflammatory cutaneous disease caused by environmental triggers in genetically predisposed individuals which account for 2–3% of the world population. However, the mechanisms contributing to the initialization of psoriasis are largely unknown. ATP is a particularly interesting candidate that, via P2X7 receptor (P2X7R) signaling, can activate NF-κB and the IL-23/IL-17 axis, both of which have been shown to be critical in psoriasis pathogenesis. Moreover, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. Specifically, we have determined that the canonical P2X7R variant A (P2X7RA) is expressed comparably in both lesional psoriatic tissues and normal human skin. However, it is the alternatively spliced P2X7R variant B (P2X7RB) that is highly expressed in human psoriatic lesions. P2X7RB is widely distributed in human tissues and P2X7RB activation enhances cellular proliferation, decreases ATP-induced apoptosis, and in heterotrimers potentiates the inflammatory responses induced by P2X7RA. Importantly, our studies have established that signaling through the P2X7R induces an acute psoriasiform dermatitis in mice. Thus, our ongoing work is focusing on the specific role of P2X7R variants in inflammatory diseases. We confirmed in human blood derived DCs that signaling through the P2X7RB can induce proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, to same degree as P2X7RA. In conclusion, this work provides a basic mechanistic insight into local inflammation induced following purinergic signaling through the P2X7R that is likely involved in the pathogenesis and potential treatment of many cutaneous inflammatory diseases.

085 TRPV1 and TRPA1 regulate dermal inflammation and epidermal hyperplasia in imiquimod (IMQ)-mediated psoriasiform dermatitis

085 TRPV1 and TRPA1 regulate dermal inflammation and epidermal hyperplasia in imiquimod (IMQ)-mediated psoriasiform dermatitis

938 Heme oxygenase-1 has a protective role in murine imiquimod-induced psoriasiform dermatitis

938 Heme oxygenase-1 has a protective role in murine imiquimod-induced psoriasiform dermatitis