Target For Treatment Of Psoriasis Research Articles

Lipoxin A4 Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis via Promoting the Regression of Inflammation.

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. 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. 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. LXA4 significantly ameliorates IMQ-induced psoriasis-like inflammation, and LXA4 can be used as a target for psoriasis treatment.

Extracellular CIRP Upregulates Proinflammatory Cytokine Expression via the NF-kappaB and ERK1/2 Signaling Pathways in Psoriatic Keratinocytes

Psoriasis is a chronic inflammatory skin disease, and elevation of proinflammatory cytokine levels is a critical driver of the pathogenesis of psoriasis. Extracellular cold-inducible RNA-binding protein (eCIRP) has been shown to play a role in various acute and chronic inflammatory diseases. C23, a short peptide derived from CIRP, competitively binds CIRP receptors and reduces damage in inflammatory diseases. However, the effect of eCIRP in psoriasis has not been studied. In the present study, we investigated the role of eCIRP in the expression of proinflammatory cytokines in keratinocytes. Our data show that eCIRP expression was increased in the sera of psoriasis patients and imiquimod- (IMQ-) induced psoriatic mice and cells stimulated with proinflammatory cytokines (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α; mix M5). Recombinant human CIRP (rhCIRP) promoted the expression of the proinflammatory cytokines TNF-α, IL-6, and IL-8 and the activation of NF-kappaB (NF-κB) and ERK1/2 in cultured keratinocytes. We then found that the above effects of eCIRP could be blocked by C23 in both normal keratinocytes and M5-stimulated psoriatic keratinocytes. In addition, in vivo experiments revealed that C23 could effectively ameliorate IMQ-induced psoriatic dermatitis. TNF-α and IL-6 mRNA expressions were reduced in the skin lesions of mice with C23-treated IMQ-induced psoriasis, and this effect was accompanied by inhibition of the NF-κB and ERK1/2 signaling pathways. In summary, eCIRP plays an important role in the pathogenesis of psoriasis and may become a new target for psoriasis treatment.

HSP90 inhibitor RGRN-305 for oral treatment of plaque-type psoriasis: efficacy, safety and biomarker results in an open-label proof-of-concept study.

HSP90 is a downstream regulator of tumour necrosis factor (TNF)-α and interleukin (IL)-17A signalling and may therefore serve as a novel target in the treatment of psoriasis. This phase Ib proof-of-concept study was undertaken to evaluate the safety and efficacy of a novel HSP90 inhibitor (RGRN-305) in the treatment of plaque psoriasis. We conducted an open-label, single-arm, dose-selection, single-centre proof-of-concept study. Patients with plaque psoriasis were treated with 250 mg or 500 mg RGRN-305 daily for 12 weeks. Efficacy was evaluated clinically using the Psoriasis Area and Severity Index (PASI), body surface area (BSA), Physician's Global Assessment (PGA) scores and the Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8 and 12 weeks after initiation of treatment were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, electrocardiogram and physical examinations. Six of the 11 patients who completed the study responded to RGRN-305 with a PASI improvement between 71% and 94%, whereas five patients were considered nonresponders with a PASI response < 50%. No severe adverse events were reported. Four of seven patients treated with 500 mg RGRN-305 daily experienced a mild-to-moderate exanthematous drug-induced eruption owing to the study treatment. Two patients chose to discontinue the study because of this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNF-α and IL-17A signalling pathways and normalization of both histological changes and psoriatic lesion gene expression profiles in patients who responded to treatment. Treatment with RGRN-305 showed acceptable safety, especially in the low-dose group, and was associated with clinically meaningful improvement in a subset of patients with plaque psoriasis, indicating that HSP90 may serve as a novel future target in psoriasis treatment.

Mannan-binding lectin exacerbates the severity of psoriasis by promoting plasmacytoid dendritic cell differentiation via the signal transducer and activator of transcription 3-interferon regulatory factor 8 axis.

Psoriasis is a chronic inflammatory skin disease mediated by host immune responses. Plasmacytoid dendritic cells (pDC) and interferon (IFN)-α secreted by pDC are involved in the initiation of psoriasis. Mannan-binding lectin (MBL), a vital component of the complement pathway, plays a critical role in innate immune defense and the inflammatory response. Our previous study found that MBL could exacerbate skin inflammation in psoriatic mice, but the effect of MBL on pDC remains unstudied. Herein, we revealed that the circulating level of MBL was elevated in patients with psoriasis compared with the healthy controls. Moreover, the MBL level was positively correlated with disease severity, relative inflammatory cytokine levels, and peripheral blood (PB) pDC frequency in psoriasis. An in vitro study determined that the MBL protein could promote the differentiation of human pDC and upregulate the production of relative inflammatory cytokines and chemokines. Additionally, MBL-deficient (MBL-/- ) mice exhibited decreased accumulation of pDC in lymph nodes, spleens, and skin lesions with reduced secretion of pDC-related cytokines compared with wild-type (WT) mice in the preliminary stage of psoriasis induced by imiquimod. Notably, the differentiation of pDC from bone marrow (BM) cells derived from MBL-/- mice was weakened compared with that from WT mice upon Fms-like tyrosine kinase 3 ligand (Flt3L) incubation. Mechanistic research indicated that the signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 8 (IRF8) axis was responsible for MBL-modulated pDC differentiation. In summary, these results suggest that MBL exacerbates the severity of psoriasis by enhancing pDC differentiation and pDC-related cytokine secretion via the STAT3-IRF8 axis, thus providing a new target for psoriasis treatment.

RPL22 Overexpression Promotes Psoriasis-Like Lesion by Inducing Keratinocytes Abnormal Biological Behavior.

BackgroundKeratinocytes of psoriasis have anti-apoptotic properties including delayed apoptosis process, accelerated proliferation metabolism and postponed differentiation process. However, the specific mechanism leading to the abnormal biological behavior of keratinocytes remains unclear.ObjectivesWe investigated the role of increased RPL22 expression in regulating the abnormal biological behavior of keratinocytes and the mechanism of regulation of RPL22 expression in skin lesions of psoriatic patients.MethodsWe examined clinical samples and utilized cytokine-induced cell and IMQ-treated mouse models. We determined the expression and functions of RPL22 in vitro and in vivo.ResultsWe showed that RPL22 expression was significantly increased in the skin lesions of psoriasis patients and IMQ-treated psoriatic-like mice. Such increased expression is attributed to hyperacetylation of histone H3K27 in the promoter region of RPL22. Interestingly, overexpression of RPL22 enhanced keratinocyte proliferation by increasing cyclinD1 expression and accelerated CD4+T cells recruitment via upregulating CXCL10 expression. Finally, we demonstrated that RPL22 overexpression promoted psoriasiform phenotypes in IMQ-induced mouse skins.ConclusionsThese findings suggested that RPL22 regulates keratinocytes abnormal biological behavior and contributes to the development of psoriatic phenotypes. Thus, RPL22 might be a novel potential molecular target for treatment of psoriasis.

Overexpression of Wilms tumor 1 promotes IL-1β expression by upregulating histone acetylation in keratinocytes

Psoriasis is a common inflammatory skin disease. Infiltration of inflammatory cells and excessive proliferation of keratinocytes are the histopathological markers of psoriasis. The transcription factor Wilms Tumor 1 (WT1) is overexpressed in several tumor types, and plays an important part in the proliferation and apoptosis of cells. Studies have found that, compared with normal skin, WT1expression in the skin lesions of patients with psoriasis are increased significantly. Knockdown of WT1 inhibited the proliferation of a human epidermal keratinocyte cell line (HaCaT cells) and promoted their apoptosis, whereas WT1 overexpression exhibited the opposite effect. WT1 was overexpressed or inhibited in HaCaT cells by transfection with the WT1 plasmid or WT1 small interferring RNA (siRNA) using Lipofectamine 2000. Transcriptome sequencing and bioinformatics analysis revealed significant differences in IL-1β expression between the experimental group and control group. Real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assays showed that expression of IL-1β and WT1 were consistent. Subsequently, IL-1β was demonstrated to be a target of WT1 by chromatin immunoprecipitation (ChIP)-sequencing and luciferase reporter assay. ChIP-qPCR showed that WT1 regulated IL-1β expression by altering acetylation. Expression of WT1 mRNA was positively correlated with expression of IL-1β mRNA in psoriatic skin lesions. Our study suggested that WT1 likely promotes psoriasis development by regulating its target gene IL-1β, which shows high expression in psoriatic lesions and is involved in psoriasis development. These findings provide a new target for psoriasis treatment.

Novel Therapeutic Approaches and Targets for Treatment of Psoriasis

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Novel Therapeutic Approaches and Targets for Treatment of Psoriasis

Novel Therapeutic Approaches and Targets for Treatment of Psoriasis

MST1 modulates Th17 activation in psoriasis via regulating TLR4-NF-κB pathway.

Psoriasis is a chronic inflammatory skin disease which mainly involves immune system. This research was to investigate the role of MST1 in the psoriasis, and the detailed mechanism whether related with Th17 and NF-κB. The skin samples and peripheral blood were obtained from psoriasis patients. Skin samples and T cells isolated from peripheral blood of patients were cultured in vitro. The results showed that the level of MST1 in the lesional skin of all three patients was higher than that of un-lesional skin, as well as the amount of CD4, CD8 and IL17 positive T cells. The amount of circulating Th17 was higher than that of control. The level of MST1, IL-17, IL-22 and TNFα was enhanced in activated T cells (p < 0.01), which indicated that MST1 increased markedly in activated T cells. The proliferation and migration of T cells were decreasing in MST1 knockdown cells, while increasing in overexpressed cells, as well as the production of IL-17, IL-22 and TNFα. MST1 enhanced the activation of TLR4-NF-κB signaling pathway, and TLR4 knockdown could reverse the effect of MST1 on NF-κB activation. This research indicated that MST1 could regulate the activation of Th17 in psoriasis partly through TLR4-NF-κB pathway. MST1 may be a target for treatment of psoriasis.

Novel Therapeutic Approaches and Targets for Treatment of Psoriasis.

Psoriasis is a multifactorial immune-mediated inflammatory disease, with a chronic relapsing-remitting course, which affects 2-3% of the worldwide population. Psoriasis involves skin, joints, or both, and it is associated with several comorbidities, including metabolic, rheumatological, cardiovascular, psychiatric complications, and other chronic inflammatory diseases, which are the expression of the complex underlying pathogenetic mechanism. An accurate characterization of the immune pathways involved in psoriasis led to recognize the new molecules, (IL)17 and 23, which become the new target of biologic therapy for moderate-to-severe plaque psoriasis. The aim of this study is to collect data of literature about IL-17 and IL-23 inhibitors. A descriptive review was conducted to identify the main data in the literature evaluating novel biologic treatments currently available: IL-17 inhibitors (secukinumab, ixekizumab and brodalumab) and IL-23 inhibitors (guselkumab, tildrakizumab and risankizumab). Dosing regimens, administration, efficacy, real-life efficacy and safety of IL-17 and IL-23 inhibitors are discussed in detail. Currently approved novel biologic therapies for moderate to severe psoriasis revealed increasing effectiveness compared to previous biological therapy and a good safety profile.

MiR-203 promotes HaCaT cell overproliferation through targeting LXR-α and PPAR-γ

ABSTRACT Psoriasis is an immune-mediated chronic inflammatory skin disease. Keratinocyte hyperproliferation has been regarded as a significant event in psoriasis pathogenesis. Considering the vital role of miRNA-mediated mRNA repression in psoriasis pathogenesis, in the present study, we attempted to investigate the mechanism of keratinocyte overproliferation from the point of miRNA-mRNA regulation. Both online microarray expression profiles and experimental results indicated that the expression of LXR-α and PPAR-γ was downregulated in psoriasis lesion skin. LXR-α or PPAR-γ overexpression alone was sufficient to inhibit keratinocyte proliferation, decrease KRT5 and KRT14 protein levels and increase KRT1 and KRT10 protein levels. miR-203 negatively regulated LXR-α and PPAR-γ expression through direct targeting. miR-203 inhibition exerted the opposite effects to LXR-α or PPAR-γ overexpression on HaCaT cells. More importantly, LXR-α or PPAR-γ overexpression could markedly remarkably attenuate the effects of miR-203 overexpression in keratinocytes, indicating that miR-203 promotes keratinocyte proliferation by targeting LXR-α and PPAR-γ. In conclusion, the miR-203-LXR-α/PPAR-γ axis modulates the proliferation of keratinocytes and might be a novel target for psoriasis treatment, which needs further in vivo investigation.

Epigenetics of Psoriasis.

Psoriasis is a chronic and recurrent inflammatory skin disease, involving the rapid proliferation and abnormal differentiation of keratinocytes and activation of T cells. It is generally accepted that the central pathogenesis of psoriasis is a T cell-dominant immune disorder affected by multiple factors including genetic susceptibility, environmental factors, innate and adaptive immune responses, etc. However, the exact etiology is largely unknown. In recent years, epigenetic involvements, such as the DNA methylation, chromatin modifications, and noncoding RNA regulation are reported to be critical for the pathogenesis of psoriasis. However, the interplay between these factors has only recently been started to be unraveled. Notably, inhibitors of enzymes that work in epigenetic modifications, such as DNA methyltransferases and histone deacetylases, are beginning to appear in the clinical setting to restore normal epigenetic patterns (Generali et al. in J Autoimmun 83:51-61, 2017), providing novel therapeutic potential as novel treatment targets for psoriasis. Indeed, medications previously used to treat autoimmune diseases have later been discovered to exert their action via epigenetic mechanisms. Herein, we review the findings on epigenetics associated with psoriasis, and discuss future perspectives in this field.

Immunohistochemical expression of hypoxia-inducible factor-1 alpha in psoriatic patients

Introduction Psoriasis is a chronic inflammatory skin disease characterized by aberrant differentiation and excessive growth of keratinocytes, with dermal and epidermal mixed leukocytic infiltrate and angiogenesis in the dermis. Oxygen consumption could be increased by the proliferation of cells, and impaired oxygen supply might occur from the thickening of the epidermis. A primary role in the maintenance of oxygen and energy homeostasis is hypoxia-inducible factor-1 (HIF-1). Several gene expression-encoding inflammatory proteins are stimulated by HIF-1. The pathogenesis of various forms of inflammation shows the involvement of hypoxia. Aim This immunohistochemical study was done to evaluate the role of HIF-1α in the pathogenesis of psoriasis. Patients and methods This study was conducted on 20 patients with chronic plaque psoriasis, and 10 healthy individuals as a control group. They underwent hematoxylin and eosin staining and immunohistochemical staining detection of HIF-1α expression. Results Regarding the correlation between HIF-1α expression and clinical parameters of the patients, there was a statistically significant positive correlation with the Psoriasis Area and Severity Index score. Conclusion In this study, there was significantly increased HIF-1α expression in psoriatic patients’ skin in comparison with normal control, and also its increase with elevated Psoriasis Area and Severity Index score might represent new promising therapeutic approaches and pharmacological research target for psoriasis treatment.

C10orf99 contributes to the development of psoriasis by promoting the proliferation of keratinocytes

Psoriasis is a chronic, relapsing inflammatory skin disease. The pathogenesis of psoriasis is complex and has not been fully understood. C10orf99 was a recently identified human antimicrobial peptide whose mRNA expression is elevated in psoriatic human skin samples. In this study, we investigated the functional roles of C10orf99 in epidermal proliferation under inflammatory condition. We showed that C10orf99 protein was significantly up-regulated in psoriatic skin samples from patients and the ortholog gene expression levels were up-regulated in imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. Using M5-stimulated HaCaT cell line model of inflammation and a combinational approach of knockdown and overexpression of C10orf99, we demonstrated that C10orf99 could promote keratinocyte proliferation by facilitating the G1/S transition, and the pro-proliferation effect of C10orf99 was associated with the activation of the ERK1/2 and NF-κB but not the AKT pathways. Local depletion of C10orf99 by lentiviral vectors expressing C10orf99 shRNA effectively ameliorated IMQ-induced dermatitis. Taken together, these results indicate that C10orf99 plays a contributive role in psoriasis pathogenesis and may serve as a new target for psoriasis treatment.

Toll-Like Receptor-Mediated Upregulation of CXCL16 in Psoriasis Orchestrates Neutrophil Activation

Innate immune processes are central in the development of the chronic inflammatory skin disease psoriasis. Studying stimulation of keratinocytes, monocytes, and dendritic cells by type I interferons or ligation of Toll-like receptors 1/2, 2/6, or 7, but not 7/8, resulted in enhanced surface expression and secretion of CXC chemokine ligand (CXCL) 16. The corresponding CXC chemokine receptor 6 was expressed on neutrophils whose recruitment into skin is important, especially in early psoriatic disease. Using the recently developed technique real-time deformability cytometry demonstrated that CXCL16 and IL-8 decreased the stiffness and enhanced deformation of neutrophils facilitating transmigration through vessel wall. In addition, CXCL16 potently induced migration of neutrophils and enhanced the chemotactic effect of IL-8. The positive feedback loop was supported by IL-8 enhancing CXCL16 production of neutrophils. Blocking of CXCL16 expression by effective treatment of psoriasis patients with tumor necrosis factor-α blockers further supported the pathogenic role of this chemokine. In summary, the data link innate immune stimulation to CXCL16 upregulation and neutrophil infiltration into skin. CXCL16 could therefore represent a potent future target for treatment of psoriasis.

LB969 Preliminary validation of the IL-36 receptor as a target in psoriasis treatment

LB969 Preliminary validation of the IL-36 receptor as a target in psoriasis treatment

Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis.

The development of monoclonal antibodies targeting IL-12 and IL-23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL-23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti-IL-23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti-IL-23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL-17 inhibitors with a favourable short-term safety profile. The results of the phase III trials support the notion that IL-23 is a potential target in psoriasis treatment.

MiR-330 inhibits IL-22-induced keratinocyte proliferation through targeting CTNNB1

Psoriasis is a common chronic inflammatory skin disease which is characterized by hyperproliferation and aberrant differentiation of keratinocytes; however the exact pathogenesis is largely unknown. Interleukin-22 (IL-22) has demonstrated its vital role in T cell-mediated immune response by interacting with keratinocytes in the pathogenesis of psoriasis. The microRNAs (miRNAs) are a class of small non-coding RNA molecules that play important roles in cellular processes by regulating gene expression at the post-transcriptional level. MiR-330 has been reported to inhibit the proliferation and migration of mouse keratinocytes. In the present study, we indicated that miR-330 expression in lesion tissue of psoriasis patients was specifically down-regulated, and could inhibit IL-22-induced proliferation of HaCaT and HKC cell. Wnt/β-catenin pathway plays an essential role in the pathogenesis of psoriasis. By direct targeting CTNNB1, miR-330 could significantly downregulate IL-22-induced CTNNB1 expression. In addition, we found that the downstream targets of β-catenin, CyclinD1 and Axin2, could be affected by miR-330; miR-330 could suppress CyclinD1 protein expression and rescue Axin2 protein expression. Taken together, we indicated miR-330 inhibits IL-22-induced proliferation of HaCaT and HKC cell by targeting CTNNB1 and subsequently affect the downstream factors, CyclinD1 and Axin2 for the first time, and provide diagnostic markers and a novel target for psoriasis treatment.

MiR-150 regulates human keratinocyte proliferation in hypoxic conditions through targeting HIF-1α and VEGFA: Implications for psoriasis treatment.

Psoriasis is a common and chronic autoimmune skin disease which affects 2 to 3% of the world population. Abnormal proliferation of human keratinocytes is an important feature of psoriasis, along with local hypoxia and vascular abnormal growth. To leverage recent molecular findings into the personalized treatment of psoriasis, we need a strategy that integrates clinical stratification with molecular phenotyping. MicroRNAs (miRNAs) are a large family of small non-coding RNA which regulates diverse biological process, including cell proliferation, by modulating gene expression at the posttranscriptional level. In the present study, we indicated that miR-150 specifically down-regulated expressed in psoriatic skin lesions, and could inhibit HaCaT cells and primary adult human keratinocytes (HKCs)’ proliferation in either normal or hypoxia conditions; by direct targeting, miR-150 could also regulate the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA). In addition, we found that HIF-1α and VEGFA were highly expressed in the lesional psoriatic skin compared with the non-lesional psoriatic skin, and negatively correlated with miR-150 expression. Taken together, we indicated miR-150 regulates human keratinocytes’ proliferation in hypoxic conditions through targeting HIF-1α and VEGFA in psoriasis for the first time, and provide diagnostic markers and a novel target for psoriasis treatment.

Article Commentary: New Treatment Targets for Psoriasis: Steering Patients and Providers toward Better Treatment Outcomes

Article Commentary: New Treatment Targets for Psoriasis: Steering Patients and Providers toward Better Treatment Outcomes