Psoriasis-like Lesions Research Articles

4'-O-β-D-glucosyl-5-O-methylvisamminol ameliorates imiquimod-induced psoriasis-like dermatitis and inhibits inflammatory cytokines production by suppressing the NF-κB and MAPK signaling pathways.

Psoriasis is a chronic inflammatory skin disorder in humans, and the inflammatory reaction plays an important role in development and onset of psoriasis. 4'-O-β-D-glucosyl-5-O-methylvisamminol (4GMV) is one of the major active chromones isolated from Saposhnikoviae divaricata (Turcz.) Schischk, which has been reported to exhibit excellent anti-inflammatory activities. However, the possible therapeutic effect on psoriasis and underlying mechanism has not been reported. Thus, the aim of this study was to investigate the protective effect of 4GMV on the imiquimod (IMQ)-induced psoriasis-like lesions in BALB/c mice and the anti-inflammatory effect on the lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. The results demonstrated that 4GMV decreased IMQ-induced keratinocyte proliferation and inflammatory cell infiltration. Moreover, 4GMV treatment significantly inhibited the production of NO, PEG 2, and cytokines such as interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and IL-22 in LPS-stimulated RAW264.7 macrophages. 4GMV also suppressed the LPS-upregulated protein expressions of iNOS and COX-2 in a dose-dependent manner. Furthermore, qRT-PCR analysis showed that 4GMV down-regulated the mRNA level of IL-1β and IL-6 expression. Further studies by western blot indicated that 4GMV inhibited the activation of upstream mediator NF-κB by suppressing the expression of TLR4 and the phosphorylation of IκBα and p65. The phosphorylation of JNK, p38, and ERK were also markedly reversed by 4GMV in LPS-treated RAW264.7 macrophages. Taken together, these results demonstrated that 4GMV showed a protective effect in IMQ-induced psoriasis-like mice and inhibited inflammation through the NF-κB and MAPK signaling pathways, indicating that 4GMV might be a potential therapeutic drug for psoriasis.

Tussilagonone Ameliorates Psoriatic Features in Keratinocytes and Imiquimod-Induced Psoriasis-Like Lesions in Mice via NRF2 Activation

Psoriasis is a common inflammatory skin disorder that is characterized by keratinocyte hyperproliferation and abnormal differentiation, resulting in the thickening of the epidermis and stratum corneum. In this study, we investigated invitro and invivo pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on transcription factors relevant for the pathogenesis of psoriasis. TGN inhibited activation of NF-κB and STAT3, leading to the attenuated expression of psoriasis-related inflammatory genes and suppression of keratinocyte hyperproliferation. Mechanistically, we show that the inhibition of NF-κB and STAT3 by TGN is mediated through activation of the cytoprotective transcription factor NRF2. Evaluation of invivo antipsoriatic effects of topical TGN in the imiquimod-induced psoriasis-like dermatitis mouse model demonstrated amelioration of imiquimod-induced phenotypical changes, lesion severity score, epidermal thickening, and reduction in dermal cellularity. The spleen index also diminished in TGN-treated mice, suggesting anti-inflammatory properties of TGN. Moreover, TGN significantly attenuated the imiquimod-induced mRNA levels of psoriasis-associated inflammatory cytokines and antimicrobial peptides and reduced epidermal hyperproliferation. Taken together, TGN, as a potent NRF2 activator, is a promising therapeutic candidate for the development of antipsoriatic agents derived from medicinal plants.

Fractional Laser-Mediated siRNA Delivery for Mitigating Psoriasis-like Lesions via IL-6 Silencing

The poor permeability of topically applied macromolecules such as small interfering RNA (siRNA) has inhibited the translation to clinical application. In this study, the fractional CO2 laser-assisted approach was developed to describe siRNA permeation enhancement mediated by the created microchannels for silencing the gene to treat psoriasiform lesions. In vitro permeation using Franz cell and in vivo interleukin (IL)-6 silencing using psoriasis-like plaque in mice were evaluated to verify the impact of the laser irradiation. Low-fluence laser exposure enabled a significant increase in skin transport of siRNA, peptide, and 5-fluorouracil (5-FU). The laser treatment resulted in the enhancement of siRNA flux by 33- and 14-fold as compared to the control in nude mouse and pig skin, respectively. The laser exposure also promoted siRNA penetration across psoriatic and photoaging skins with the deficient barrier, although the enhancement level was minor compared to that of intact skin. The 3D images of confocal microscopy revealed a diffusion of macromolecules into the laser-created microchannels; the radial and vertical distribution to the surrounding and deep tissues followed this. A single laser treatment and the following topical siRNA administration were able to reduce IL-6 expression by 64% in the psoriatic skin model. Laser assistance led to the marked improvement in the plaque and the reduction of specific cytokine expression, keratinocyte proliferation, and neutrophil infiltration. Our data support the use of the fractional laser for delivery of functional nucleic acid into the skin and the target cells.

A unique case of borderline lepromatous leprosy with psoriasis-like lesions all over the body and mycosis fungoides-like lesions on the face

sClinical manifestations of leprosy are various and may resemble other skin diseases. Skin lesions of leprosy mimicking psoriasis and mycosis fungoides (MF) that simultaneously occurs in one patient are rare. We reported a unique case of borderline lepromatous (BL) leprosy with severe reversal reaction manifested as psoriasis-like lesions and MF-like lesions in a 43-year-old-man. Psoriasis-like lesions all over the body accompanied by plaques and tumor-like lesions mimicking MF on the face could be found in this patient. Histopathological examination on an MF-like lesion from the face and psoriasis-like lesions from the posterior trunk and lower extremities revealed granulomatous reaction with epithelioid cells, Langhans giant cells, and foam cells which supported the diagnosis of BL leprosy. The patient was treated with multidrug therapy multibacillary (MDT-MB) regimen and 40 mg prednisone daily which was tapered off. Clinical improvement was observed on the 32nd day of observation as psoriasis-like and MF-like lesions became hyperpigmented macules and plaques, respectively. Due to the rarity of the multitype skin lesions of leprosy in one patient, a diagnosis of leprosy should be suspected by the clinicians in any patients with previously described skin disorders, especially in an endemic area.

ALA-PDT alleviates the psoriasis by inhibiting JAK signalling pathway.

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is a well-known treatment for non-hypertrophic actinic keratoses and superficial basal-cell carcinomas. In this study, we first revealed that ALA-PDT treatment effectively ameliorated the psoriasis-like lesion in imiquimod (IMQ)-induced mouse model and further explored the potential molecular mechanism and related signalling pathways during the treatment. Besides, we also confirmed a significant alleviation of ALA-PDT therapy on IFN-γ-induced over-proliferation of keratinocytes. H&E staining was conducted to reveal the histological changes of mice in different groups. The different expression levels of RNA were illustrated by using QRT-PCR. Western blot was performed to confirm the various expression levels of protein in mice. In vitro, cell proliferation and cell cycle were evaluated by cell counting kit-8 and flow cytometry assay, respectively. The result showed that ALA-PDT's anti-proliferation effect and regulation on Socs1/3, JAK1/2 and K17 in IFN-γ-induced keratinocytes were largely weakened by NAC, indicating that ALA-PDT attenuated the proliferation of IFN-γ-induced keratinocytes by enhancing ROS level. These results demonstrated that ALA-PDT largely activated the productivity of Socs1/3 in a ROS-dependent manner. Socs1/3 is a potential blocker in JAK signalling pathway and inhibits the proliferation and keratinization of keratinocytes in psoriasis.

391 Ruxolitinib cream is highly effective at modulating a humanised rodent model of psoriasis vulgaris

Psoriasis is a chronic, immune-mediated disorder with cutaneous and systemic manifestations resulting in substantial negative impact on patient quality of life. Psoriasis pathophysiology involves abnormal keratinocyte proliferation, infiltration of T helper (Th)17, Th1 and Th22 lymphocytes and secretion of proinflammatory cytokines interleukin (IL)-17, IL-22, interferon (IFN)γ, and tumor necrosis factor (TNF)a. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a critical mechanism for multiple inflammatory mediators. Ruxolitinib cream, a topical JAK1/2 inhibitor, has previously been reported to be efficacious in clinical trials for the treatment of plaque psoriasis (NCT00778700 & NCT00820950). The goal of these preclinical studies was to elucidate the biological mechanisms that underpin the efficacy of Ruxolitinib cream in Th1 / Th17 mediated inflammatory skin diseases. Non-lesional skin biopsies were obtained from psoriasis patients and transplanted onto immunodeficient mice. Three weeks after transplantation, mice were injected intra-dermally with the donors’ super-antigen-activated peripheral blood mononuclear cells (PBMCs) to develop a psoriasis-like lesion of the transplanted biopsy. Ruxolitinib cream (1.5% w/v) was administered daily after injection of patient PBMCs. Efficacy readouts included depth of reti-ridges (papillae), Ki67 positive keratinocytes and inflammatory pathway analysis. Ruxolitinib cream (1.5% w/v) treatment significantly reduced skin thickening in the psoriatic lesion biopsy, and this was associated with reduced keratinocyte proliferation. Conclusion: Ruxolitinib cream (1.5% w/v) topically administered is highly effective at reducing multiple lesional parameters in this Th1 / Th17 dependent humanised rodent model of psoriasis vulgaris.

Acupuncture Needling, Electroacupuncture, and Fire Needling Improve Imiquimod-Induced Psoriasis-Like Skin Lesions through Reducing Local Inflammatory Responses

Psoriasis is a common autoimmune disease. Acupuncture-related techniques have been widely used to treat psoriasis since its ability to engage neuronal function, the immune system, and other systems is well documented. This study aimed to investigate and compare the effects of three common acupuncture-related techniques in psoriasis-like skin inflammatory responses and explore the possible involved mechanisms. Imiquimod (IMQ)-induced psoriasis-like mice were treated with acupuncture needling, electroacupuncture, or fire acupuncture. Methotrexate (MTX) was applied as a positive control. Scoring by the psoriasis area and severity index (PASI) evaluated skin lesion changes. Keratinocyte proliferation and inflammatory cell infiltration were investigated using pathological staining. The secretion levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The expression levels of neuropeptides were assessed by Western immunoblotting. We found that acupuncture needling, electroacupuncture, and fire acupuncture all ameliorated skin lesions, reduced epidermal thickness, inhibited keratinocyte proliferation, and reduced CD3+ T cell infiltration. The aforementioned acupuncture techniques also decreased inflammatory cytokine secretion, including IL-1β, IL-17A, and IL-23p40. Among them, electroacupuncture showed the best curative effects. Additionally, electroacupuncture downregulated the expression levels of Neurokinin A (NKA), which was positively associated with decreased inflammatory cytokine levels in local lesions. In conclusion, acupuncture needling, electroacupuncture, and fire acupuncture alleviated IMQ-induced psoriasis-like lesions. By contrast, electroacupuncture was more beneficial in reducing the inflammatory response, which might be related to locally dampened neuropeptide levels. Observations support the therapeutic effect of acupuncture for psoriasis and indicate a neuromodulatory mechanism in treating psoriasis by electroacupuncture.

669 Paeoniflorin suppresses keratin 17 expression via NF-kB pathway and exerts anti-psoriatic effect

Psoriasis, affecting 2%-3% of the population worldwide, is an autoimmune inflammatory skin disease characterized by hyperproliferation of epidermal keratinocytes. Regarding the complexity of disease pathogenesis, there is still no curative therapy for psoriasis. Paeoniflorin (PF), a traditional Chinese herbal medicine, which is the main bioactive component of the total glucosides of peony, is extracted from Paeonia lactiflora Pall (Family: Ranunculaceae). This agent has been shown to have various pharmacological effects, including anti-inflammatory, anti-phlogistic, and anti-apoptotic effects. In the present study, we aimed to illustrate the effect and mechanism of PF on keratinocyte proliferation and immunological activity. In IMQ-induced psoriasis-like lesions, epidermal thickness was reducing to 50% as compared with control groups after topical application of PF. Consistently, dermal infiltrated lymphocytes was markedly reduce. Here we showed that PF could inhibit the proliferation of human keratinocyte cell line HaCaT in a dose-dependent manner. To further clarify the related mechanism, we evaluated the effect of PF on the expression of psoriasis-related hyperproliferation marker K17. Interestingly, K17 protein and mRNA levels were significantly downregulated in HaCaT cells after application of PF. Besides, PF showed inhibitory effect on the inflammatory function of keratinocytes, representing by reduced activation of NF-kB signaling pathways, such as phosphorylated NF-kB p65 and phosphoryalated-IkB. Together, our findings uncovers a previous unrecognized role of PF on inhibiting the proliferation and inflammation of keratinocytes by targeting K17, suggesting that PF might be a potential target in the treatment of psoriasis.

Oleic acid as the active agent and lipid matrix in cilomilast-loaded nanocarriers to assist PDE4 inhibition of activated neutrophils for mitigating psoriasis-like lesions

Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids show anti-inflammatory activity for treating inflamed skin diseases, but their efficacy remains low. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis model. OA played dual roles in the nanocarriers as both the active ingredient and lipid matrix in the nanoparticulate core. OA nanoparticles but not free OA could restrain calcium mobilization in activated neutrophils. The inhibition level of superoxide anion and elastase by cilomilast-loaded OA nanocarriers approximated that of free forms. In the mouse model, the intradermal nanosystems reduced imiquimod-induced epidermal thickening from 230.4 to 63.1 μm. Transepidermal water loss was decreased from 30.2 to 11.3 g/m2/h by integrated nanocarriers. The nanosystems mitigated neutrophil infiltration and hyperproliferation in the psoriasiform lesion via decreased expression of cytokines and chemokines. Statement of SignificanceThe long-term therapy for psoriasis is unsatisfactory due to the possible adverse effects and inefficiency after prolonged use. Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids such as oleic acid (OA) show anti-inflammatory activity for treating inflamed skin diseases. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. OA is also ideal for incorporation into nanoparticles to enhance particulate emulsification, drug entrapment, and biocompatibility. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis lesion. OA nanocarriers are indigenous to prevent neutrophil activation and the deterioration of psoriatic lesion. Cilomilast incorporation in OA nanocarriers could further mitigate the clinical score and suppressing proinflammatory mediators.

Components analysis and anti-psoriatic effect of standard decoction of Lithospermum

Objective To analyze the main ingredients and investigate the anti-psoriasis effect in the standard decoction of Lithospermum. Methods The extraction rate was determined by extract determination method, and the content of total polysaccharide and total phenolic acid was evaluated by spectrophotometry. Moreover, the effects of different concentrations of the standard decoction of Lithospermum on skin lesions induced by imiquimod (IMQ) in psoriatic mice were observed. Results The extracting rate was 4.65 %, the total polysaccharide content was 1.182 mg/ml and the total phenolic acid content was 3.506 mg/ml. The different concentrations of the standard decoction of Lithospermum could ameliorate the scales, erythema and psoriasis-like mice skin and reduce the thickness of epidermis. Conclusions The standard decoction of Lithospermum could improve the psoriasis-like lesions induced by imiquimod in mice and possess the anti-psoriasis effect. Key words: Arnebiae radix; Standard decoction; Polysaccharides; Phenolic acid; Psoriasis

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

BackgroundIL-36γ is considered to be a valuable biomarker in psoriatic patients, which is expressed as an inactive precursor that needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36γ.ObjectivesThis study aims to investigate the activation of IL-36γ by cathepsin G (CG) and neutrophil elastase (NE).Materials and methodsWe used inactive recombinant full-length (FL)-IL-36γ with different doses of NE or CG to stimulate HaCaT cells; neutrophil extracellular traps (NETs) were prepared to act on FL-IL-36γ and then stimulate HaCaT cells. Real-time quantitative PCR and ELISA were performed to detect CXCL-1 and CXCL-8 expression. We developed imiquimod-induced psoriasis-like mouse model to evaluate the effect of hypodermic injection of neutrophil-derived protease or its inhibitor. Histopathology and Western blotting were conducted for effect assessment.ResultsPurified CG cleaved and activated recombinant human FL-IL-36γ to promote CXCL-1 and CXCL-8 expression by human keratinocytes, and NETs activated FL-IL-36γ and the activation was inhibited by serpin A3. CG induced expression of a more truncated IL-36γ in psoriasiform lesion of mice and aggravated the psoriasis-like lesion induced by imiquimod, whereas recombinant serpin A3 alleviated the severity of the psoriasis-like mouse mode.ConclusionCG has the ability to cleave and activate IL-36γ and aggravate imiquimod-induced mouse psoriasiform lesion. Thus, CG-specific inhibitors might be promising therapeutic drugs for psoriasis.

PDRN, a Biologic Agonist of the Adenosine A <sub>2A</sub> Receptor, Ameliorates Imiquimod-Induced Psoriasis Through NF-κB Pathway Inhibition and Wnt/β-Catenin Signalling Modulation

Background: Inflammation is a key hallmark of psoriasis and pro-inflammatory cytokines are produced by the transcription factor Nuclear factor-κB (NF-κB). Canonical Wnt/β-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation either blocks NF-κB and boosts the Wnt/β-catenin signalling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Methods: Psoriasis-like lesions were induced by a topical daily application of imiquimod cream (IMQ; 62.5 mg/day for 7 days) on the shaved back skin of mice. Animals were randomly assigned to the following groups: Sham psoriasis challenged with vaseline cream; IMQ animals challenged with imiquimod and IMQ animals challenged with IMQ and treated with PDRN (8 mg/kg/ip). In histological experiments an additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. Findings: PDRN administration reduced squamous lesions, erythema, epidermal thickness and acanthosis, trying to restore a normal skin architecture. Istradefylline administration abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pNF-κB and TNF-α IL-6 and IL-12 expression compared to untreated psoriatic animals. Furthermore, A2Areceptor activation prompted Wnt signalling, reduced IL-2 expression and increased IL-10 mRNA expression in psoriatic skin. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis. Interpretations: PDRN anti-psoriasis potential may be linked to a dual mode of action: NF-κB pathway inhibition and Wnt/β-catenin signalling stimulation. Funding: The work has been performed with Departmental funding assigned to FS. Competing Interest Declaration: The authors declare that the research was conducted in the absence of any commercial or financial conflict of interest. Ethics: The procedures were evaluated and approved by the Ethics Committee of the University of Messina (OPBA, #820/2016).

A case with psoriasis-like lesions induced by olmutinib (HM61713) while treating epidermal growth factor receptor T790M mutant advanced lung adenocarcinoma

Olmutinib (HM61713) is a third-generation tyrosine kinase inhibitor active against mutant EGFR, including T790M in nonsmall cell lung cancer. The most common side effect of olmutinib to date includes diarrhea, rash, nausea, and pruritus. To the best of our knowledge, it is the first case of psoriasis-like lesions that occurred after treatment with olmutinib. Although the pathogenesis for skin manifestations is presently unknown, we present this case to increase awareness of this unique cutaneous side effect.

Three Constituents of Moringa oleifera Seeds Regulate Expression of Th17-Relevant Cytokines and Ameliorate TPA-Induced Psoriasis-Like Skin Lesions in Mice.

As a folk medicine, Moringa oleifera L. is used effectively to treat inflammatory conditions and skin diseases. However, its mechanism of action is not well understood, limiting its medical use. We isolated and identified three compounds, namely niazirin, marumoside A and sitosterol-3-O-β-d-glucoside, from the seeds of Moringa oleifera, and studied their effects on the expression of Th17-relevant cytokines (IL-12/IL-23 p40, IL-17A, IL-22 and IL-23 p19) using lipopolysaccharide-stimulated THP-1 cells. Additionally, as Th17 plays a critical role in the pathogenesis of psoriasis, we used a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced psoriasis-like skin lesion mouse model to study their potential therapeutic application in vivo. The compounds suppressed the expression of IL-12/IL-23 p40, IL-17A, IL-22 and IL-23 p19 in vitro, and in vivo they ameliorated psoriasis-like skin lesions, decreased IL-17A mRNA expression, and increased the expression of keratinocyte differentiation markers. To our knowledge, this is the first report regarding the mechanism and therapeutic application of Moringa oleifera seeds to treat psoriasis-like lesions in vivo.

Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production

BackgroundPsoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial. ObjectivesTo elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. MethodsTwo lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer. ResultsLCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23. ConclusionsOur study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.

The active compounds derived from Psoralea corylifolia for photochemotherapy against psoriasis-like lesions: The relationship between structure and percutaneous absorption

8‑Methoxypsoralen (8-MOP) in combination with ultraviolet A (PUVA) is a photochemotherapy for management of psoriasis. 8-MOP is a natural compound from Psoralea corylifolia. The present work was undertaken to evaluate the percutaneous absorption of five compounds derived from P. corylifolia, and to further explore the inhibitory effect on psoriasis-like lesions generated by imiquimod stimulation in a mouse model. 8-MOP, psoralen, isopsoralen, psoralidin, and bakuchiol were comparatively tested for in vitro skin permeation, keratinocyte apoptosis, and in vivo antipsoriatic potency. The pig ear skin deposition of 8-MOP, isopsoralen, and bakuchiol at an equimolar dose was 0.47, 0.58, and 0.50 nmol/mg, respectively, which was comparable and higher than that of psoralen (0.25 nmol/mg) and psoralidin (0.14 nmol/mg). Psoralidin and bakuchiol were absorbed into the skin without further penetration across the skin. Besides experimental data of physicochemical properties, the hydrogen bond number, total polarity surface, and stratum corneum lipid docking calculated could explain the correlation of the penetrant structure with the skin permeability. The antiproliferative activity against keratinocytes was stronger for 8-MOP and isopsoralen than the others. Topical application of PUVA by using 8-MOP and isopsoralen on imiquimod-induced plaque significantly reduced transepidermal water loss from 55 to 33 and 38 g/m2/h, respectively. The epidermal thickening elicited by imiquimod (117 μm) was decreased to 62 and 26 μm by 8-MOP and isopsoralen application. IL-6 expression in psoriasiform skin was downregulated by isopsoralen but not 8-MOP. Isopsoralen may be a potential candidate for PUVA therapy.

Chlamydial Plasmid-Encoded Protein pGP3 Inhibits Development of Psoriasis-Like Lesions in Mice.

BackgroundThe anti-microbial protein cathelicidin LL-37 plays an important role in the pathogenesis of psoriasis by inducing inflammation. Our previous study showed that the chlamydial plasmid-encoded protein pGP3 forms a stable complex with LL-37 to neutralize its pro-inflammatory activity. Here, we explored whether pGP3 can inhibit the development of lesions in mice with imiquimod-induced psoriasis.Material/MethodsThe protein pGP3 was expressed in bacteria and purified using glutathione-conjugated agarose beads and a precision protease. The ability of the purified pGP3 to block chemotaxis mediated by LL-37 was tested in vitro using bone marrow-derived neutrophils. The ability of the protein to inhibit the development of psoriasis-like lesions was tested by topically or subcutaneously administering pGP3 in doses of 10 or 50 μg to mice previously treated with imiquimod. Mouse skin was evaluated using the psoriasis area and severity index (PASI) score and photography. Skin biopsies were taken on day 8 and analyzed histologically.ResultsPurified pGP3 inhibited LL-37-mediated chemotaxis. Mice treated with 50 μg pGP3 showed clinical improvement with less severe erythema, infiltration, and scales; these mice also showed thinner dermis and less hyperkeratosis, parakeratosis, and inflammatory cell infiltration than mice treated with without 10 μg pGP3.ConclusionsPGP3 can inhibit the development of psoriasis-like lesions in mice, possibly through its ability to bind LL-37. Future work should examine the mechanisms underlying this therapeutic effect.

Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Recent studies demonstrated that the TWEAK/Fn14 signals participate in the development of psoriasis. The purpose of this study was to further explore the effect of Fn14 inhibition on experimental psoriasis. Psoriasis-like skin disease was induced in the wild-type and Fn14-knockout BALB/c mice. We found that Fn14 deficiency ameliorates psoriasis-like lesion in this model, accompanied by less inflammatory cell infiltration and proinflammatory cytokine production in lesional skin. The cutaneous expression of TNF receptor type 2 also decreased in the Fn14-deficient mice. Moreover, the topical application of TWEAK exacerbated psoriatic lesion in the wild-type but not in the Fn14-deficient mice. Furthermore, TWEAK promoted the expression of interleukin 8, keratin 17, and epidermal growth factor receptor (EGFR) but inhibited the expression of involucrin in psoriatic keratinocytes in vitro. Interestingly, such effect of TWEAK was abrogated by an EGFR inhibitor (erlotinib). TWEAK also enhances the proliferation and interleukin-6 production of dermal microvascular endothelial cells under psoriatic condition. In conclusion, TWEAK/Fn14 signals contribute to the development of psoriasis, and involves the modulation of resident cells and the transduction of the EGFR pathway. Fn14 inhibition might be a novel therapeutic strategy for patients with psoriasis.

Decryption of Active Constituents and Action Mechanism of the Traditional Uighur Prescription (BXXTR) Alleviating IMQ-Induced Psoriasis-Like Skin Inflammation in BALB/c Mice.

Bai Xuan Xia Ta Re Pian (BXXTR) is a traditional Uighur medicine ancient prescription in China widely used in the treatment of psoriasis, presenting a high curative rate and few side effects. Given that the active constituents and action mechanism still remain unclear, the aim of this study is to explore the potential active constituents and mechanism of antipsoriasis of BXXTR. Psoriasis-like lesions model in BALB/c mice was induced by Imiquimod (IMQ), including five treatment groups: control group, IMQ-treated group, IMQ-ACITRETIN group (Positive control group), IMQ-BXXTR low dose group, IMQ-BXXTR medium dose group and IMQ-BXXTR high dose group. The Psoriasis Area and Severity Index (PASI) score, skin and ear thickness, and histologic section were collected. The differentially expressed genes were determined by using RNAseq technology and the relevant pathways were analyzed by KEGG database. The ELISA kit and western blot assays were used to detect the related protein expression levels. In addition, the chemical constituents of BXXTR were determined by UPLC-TOF-MS analysis and the potential active constituents were predicted by SEA DOCK and Gene Ontology (GO). The data demonstrated that BXXTR significantly alleviated IMQ-induced psoriasis. RNA-seq analysis showed that BXXTR induced the expression levels of 31 genes; the KEGG analysis suggested that BXXTR could significantly change IL-17-related inflammatory pathways. The ELISA kit confirmed that the expression level of IL-17A protein was significantly reduced. 75 compounds of BXXTR were determined by UPLC-TOF-MS analysis, 11 of 75 compounds were identified as potential active compounds by similarity ensemble approach docking (SEA DOCK) and Gene Ontology (GO). BXXTR reduced the severity of skin lesions by inhibiting IL-17-related inflammatory pathways. The results indicated that BXXTR could suppress psoriasis inflammation by multiple-constituents-regulated multiple targets synergistically. Collectively, this study could provide important guidance for the elucidation of the active constituents and action mechanism of BXXTR for the treatment of psoriasis.

Topical heat shock protein 70 prevents imiquimod-induced psoriasis-like inflammation in mice.

Psoriasis is a chronic inflammatory skin disease with systemic manifestations and potential genetic etiology. The newest treatments utilize antibodies against one of several cytokines known to underlie the inflammatory signaling molecules that produce the skin and systemic symptoms. However, these agents must be regularly injected, and they may compromise the normal responses of the immune system. Furthermore, they do not address the causes of the abnormal immunoregulatory responses of the disease because the etiology is not yet completely understood. In this short-term treatment study, the potential anti-inflammatory activity of an alfalfa-derived Hsp70-containing skin cream (aHsp70) was tested on imiquimod (IMQ)-induced psoriasis-like lesions in wild-type mice. Treatment of the mice with the aHsp70 skin cream simultaneously with the imiquimod application mitigated the induction of psoriatic-like lesions and correlated with altered expression of various skin cytokines.