Inflammatory Psoriasis Research Articles

Qinzhu Liangxue inhibits IL-6-induced hyperproliferation and inflammation in HaCaT cells by regulating METTL14/SOCS3/STAT3 axis

Ethnopharmacological relevancePsoriasis, an immune-mediated chronic inflammatory skin condition, is treatable with Qinzhu Liangxue (QZLX), a therapeutic medicinal plant formula used in clinical practice. However, further investigation is needed to clarify its molecular mechanisms of action. Aim of the studyThe potential biological mechanisms of QZLX to alleviate psoriasis involving IL-6-induced hyperproliferation and inflammation by regulating METTL14/SOCS3/STAT3 axis. Materials and methodsHaCaT cell model was induced by IL-6, and dealt with serum containing QZLX. In addition, shRNAs and siRNAs were used for gene silencing, viruses were collected 48 h post-transfection and infected HaCaT cells. Cell viability was detected by CCK-8 assay, cell cycle was determined by flow cytometry. Finally, psoriasis mice model was induced by IMQ cream, then back skin tissue was used for hematoxylin and eosin (H&E). The content of IL-1β, IL-6, and IL-8 in cell supernatants were analyzed using ELISA kits. Analysis of SOCS3 was used by quantitative RT-PCR, the expression level of SOCS3, METTL3, METTL14, WTAP, SOCS3, YTHDF2, p-STAT3 and STAT3 in HaCaT cells transduced with METTL14 overexpression was detected by Western blot. ResultsAll results indicated that QZLX could significantly alleviate IL-6-induced HaCaT cell viability, cell cycle progression, and inhibit the level of IL-1β, IL-6, and IL-8. The m6A levels and level of METTL14 in HaCaT cells treated with IL-6 were enhanced, while it was reversed by QZLX. METTL14 silencing could inhibit IL-6-induced HaCaT cell viability, cell cycle progression and inflammation response, while SOCS3 overexpression also suppressed METTL14-induced HaCaT cell viability, cell cycle progression and inflammation. QZLX could significantly enhance the expression level of SOCS3, while inhibit the level of METTL14, and p-STAT3/STAT3. In addition, QZLX inhibits METTL14-induced HaCaT cell viability, cell cycle progression, and inhibits the level of IL-1β, IL-6, and IL-8. ConclusionsOur finding suggested that QZLX ameliorated the inflammation response of psoriasis and performed the potential anti-psoriasis effect by regulating METTL14/SOCS3/STAT3 axis in both mice and HaCaT cells psoriasis model. Therefore, our study demonstrated a significant strategy for inhibiting psoriasis inflammation via targeting METTL14/SOCS3/STAT3 axis.

Engineering extracellular vesicles with macrophage membrane fusion for ameliorating imiquimod-induced psoriatic skin inflammation

IntroductionHerein, we developed an engineered extracellular vehicle (EV)-based method for ameliorating inflammatory responses in psoriasis.MethodsEVs, derived from annexin A1 (ANXA1) overexpressing T cells, were co-extruded with M2 macrophage membrane to obtain engineered EVs. In vitro, the effect of engineered EVs on macrophage polarization was evaluated by real-time PCR. In imiquimod (IMQ)-induced psoriasis-like mouse model, the efficacy of engineered EVs in ameliorating psoriatic inflammation was evaluated by Psoriasis Area and Severity Index (PASI) score and immunohistochemistry staining after subcutaneous injection of EVs.ResultsThe engineered EVs not only preserved the high stability of M2 macrophage membrane but also retained the macrophage reprogramming potential of ANXA1 overexpressed in T cells. In the psoriasis-like mouse model, subcutaneous injection of engineered EVs successfully reduced the PASI score and the levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Along with high biosafety, the administration of EVs also rescued the histomorphological changes of spleen, liver, and kidney.ConclusionsThe engineered EVs exhibited the potential to alleviate inflammation of psoriasis, providing new insights and potential strategies for the immunotherapies of psoriasis.

IL-17A-targeting fenofibrate attenuates inflammation in psoriasis by inducing autophagy

IL-17A is a critical pro-inflammatory cytokine in autoimmune diseases such as psoriasis. Targeting of IL-17A is an effective strategy to treat patients with autoimmune diseases; however, relevant small molecule therapeutics have not yet been developed. Here, the small molecule drug fenofibrate was validated as an inhibitor of IL-17A through ELISA and surface plasmon resonance (SPR) assays. We further confirmed that fenofibrate blocked IL-17A signalings including the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, in IL-17A-treated HaCaT cells, HEKa (human primary epidermal keratinocytes) and imiquimod (IMQ)-induced psoriasis mouse model. Fenofibrate attenuated systemic inflammation by suppressing Th17 populations and inflammatory cytokines, such as IL-1β, IL-6, IL-17A, and tumor necrosis factor (TNF). Surprisingly, fenofibrate upregulated LC3 and p62 in the psoriatic mouse group. The autophagy changes were caused by ULK1 pathway in hIL-17A-treated HaCaT and HEKa. In addition, the enhancement of autophagy by fenofibrate exerted anti-inflammatory effects, as demonstrated by the suppression of IL-6 and IL-8 in the IL-17A-treated keratinocytes. Thus, IL-17A-targeting fenofibrate can be a potential therapeutic for psoriasis and other autoimmune diseases via regulating autophagy.

Cutaneous lesions in psoriatic arthritis are enriched in chemokine transcriptomic pathways

ObjectivesSkin from people with psoriasis has been extensively studied and is assumed to be identical to skin from those with psoriatic arthritis (PsA). Chemokines and the CC chemokine scavenger receptor ACKR2 are upregulated in uninvolved psoriasis. ACKR2 has been proposed as a regulator of cutaneous inflammation in psoriasis. The aim of this study was to compare the transcriptome of PsA skin to healthy control (HC) skin and evaluate ACKR2 expression in PsA skin.MethodsFull-thickness skin biopsies from HC, lesional and uninvolved skin from participants with PsA were sequenced on NovaSeq 6000. Findings were validated using qPCR and RNAscope.ResultsNine HC and nine paired PsA skin samples were sequenced. PsA uninvolved skin was transcriptionally similar to HC skin, and lesional PsA skin was enriched in epidermal and inflammatory genes. Lesional PsA skin was enriched in chemokine-mediated signalling pathways, but uninvolved skin was not. ACKR2 was upregulated in lesional PsA skin but had unchanged expression in uninvolved compared with HC skin. The expression of ACKR2 was confirmed by qPCR, and RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA lesions.ConclusionChemokines and their receptors are upregulated in lesional PsA skin but relatively unchanged in uninvolved PsA skin. In contrast to previous psoriasis studies, ACKR2 was not upregulated in uninvolved PsA skin. Further understanding of the chemokine system in PsA may help to explain why inflammation spreads from the skin to the joints in some people with psoriasis.

D-mannose blocks the interaction between keratinocytes and Th17 cells to alleviate psoriasis by inhibiting HIF-1α/CCL20 in mice.

Psoriasis is an autoimmune chronic inflammatory skin disease with an unclear pathogenesis that is difficult to cure, causing serious physical and mental burdens for patients. Previous research showed that a mutually reinforcing vicious cycle caused by keratinocytes (KC) and a variety of immune cells plays an important role in psoriatic inflammation. d-Mannose, a widely distributed metabolite in the body, has been found to treat several metabolic diseases, but its impact on psoriasis remains unknown. Our study aims to investigate the effects of d-mannose on psoriasis and its specific mechanism. Here, we found that d-mannose alleviates psoriasis in mice both as oral and topical agents. Specifically, d-mannose down-regulated the expression of hypoxia-inducible factor 1A(HIF-1α) and inhibited the expression of chemokine CCL20 in keratinocytes, thereby inhibiting the local infiltration of Th17 cells and breaking the cycle of keratinocytes-Th17 cells. Overall, our study indicates that d-mannose alleviates cutaneous inflammation in psoriasis by inhibiting the HIF-1α/CCL20/Th17 cells axis, and d-mannose has the potential to be used as an oral and topical agent in the treatment of psoriasis.

Cardiovascular comorbidity in psoriasis - psoriatic inflammation is more than just skin deep.

There is a growing understanding of inflammation in psoriasis beyond its dermatological manifestation, towards systemic inflammation. Management of possible comorbidities encompassing psychological, metabolic and cardiovascular disease is recommended in national and international dermatology guidelines for treatment of psoriasis patients. Vice versa, psoriasis is being recognized as a new risk factor for cardiovascular inflammation within the cardiological community. A review of the literature was conducted. Key points regarding epidemiological, mechanistic and management aspects were summarized and put into context for physicians treating psoriasis patients. Efforts are currently being made to better understand the mechanistic underpinnings of systemic inflammation within psoriatic inflammation. Studies looking to "hit two birds with one stone" regarding specifically cardiovascular comorbidities of psoriasis patients using established systemic dermatological therapies have so far provided heterogeneous data. The diagnosis of psoriasis entails preventive and therapeutic consequences regarding concomitant diseases for the individual patient. The knowledge of comorbidities in psoriasis calls for pronounced interdisciplinary care of psoriasis patients, to which this article highlights efforts regarding vascular inflammation and cardiovascular disease.

LncRNA UCA1 promotes keratinocyte-driven inflammation via suppressing METTL14 and activating the HIF-1α/NF-κB axis in psoriasis

Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

921 Inhibition of IARS alleviates skin inflammation in psoriasis through JAK2/STAT3 pathway

921 Inhibition of IARS alleviates skin inflammation in psoriasis through JAK2/STAT3 pathway

927 NLRP3 inflammasome contributes to the systemic inflammation in psoriasis

927 NLRP3 inflammasome contributes to the systemic inflammation in psoriasis

1326 Translation-dependent skin hyperplasia is promoted by type 1/17 inflammation in psoriasis

1326 Translation-dependent skin hyperplasia is promoted by type 1/17 inflammation in psoriasis

846 LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating STAT3 pathway and downregulating KHSRP

846 LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating STAT3 pathway and downregulating KHSRP

Translation-dependent skin hyperplasia is promoted by type 1/17 inflammation in psoriasis

BackgroundPsoriasis vulgaris (PV) is a chronic skin inflammatory disease and characterized by aberrant epidermal hyperplasia. The molecule eukaryotic initiation factor (eIF) 4E controls translation initiation of certain protein synthesis and determines cell cycle or differentiation fate. ObjectiveTo determine the role of eIF4E in keratinocytes abnormal differentiation in the context of psoriasis. MethodsThe expression of eIF4E in psoriatic skin lesions and normal skin from human subjects was examined by western blot and immunohistochemistry. In a murine model of psoriasis-like dermatitis that is induced by topical imiquimod, 4EGI-1 was used to inhibit eIF4E activities. To measure murine skin eIF4E and keratinocytes differentiation, immunofluorescence and western blot assays were conducted. Normal human epidermal keratinocytes (NHEK) were isolated, cultured, and stimulated with cytokines including TNF-α, IFN-γ, and IL-17A, respectively. Immunofluorescence and western blot were performed to test eIF4E and effect of 4EGI-1 in a co-culture system. ResultsCompared with healthy controls, skin lesions from patients with PV exhibited a higher expression of eIF4E, which was positively correlated with the epidermal thickness. This expression pattern of eIF4E was replicated by the imiquimod-induced murine model. Skin hyperplasia and eIF4E activities in the murine model were attenuated by the administration of 4EGI-1. Both IFN-γ and IL-17A, rather than TNF-α, are sufficient to induce NHEK abnormal differentiation. This effect can be disrupted by 4EGI-1. ConclusioneIF4E plays a crucial role in keratinocytes abnormal differentiation driven by type 1/17 inflammation in the context of psoriasis. The initiation of abnormal translation provides an alternative treatment target for psoriasis.

Long Non-Coding RNA-GDA-1 Promotes Keratinocyte Proliferation and Psoriasis Inflammation by Regulating the STAT3/NF-κB Signaling Pathwayvia Forkhead Box M1.

Psoriasis is a chronic inflammatory skin disease associated with multiple comorbidities and complex pathogenesis. Long non-coding RNAs (lncRNAs) play an important regulatory role in many diseases, including psoriasis. In this study, We aimed to investigate the role and mechanism of lncRNA GDA-1 (GDA) in M5-treated psoriatic keratinocytes. GDA expression was significantly upregulated in psoriatic tissues and M5-treated keratinocytes. By silencing and overexpressing GDA in NHEKs and Ker-CT cells, we showed that GDA regulated proliferation and cell cycle and increased secretion of interleukin-1β (IL-1β), IL-6, and chemokine ligands 2 and 20 (CCL2 and CCL20). RNA sequencing after GDA silencing led to the identification of a close regulatory relationship between GDA and Forkhead Box M1 (FOXM1). GDA significantly influenced FOXM1 expression at both mRNA and protein levels and activated STAT3/NF-κB signaling pathways. STAT3 and NF-κB inhibition abrogated GDA effects on keratinocyte proliferation and inflammation. In conclusion, our study is the first to report that Lnc-GDA-1 distinctly regulates FOXM1 expression and mediates proliferation and inflammation of psoriatic keratinocytes through the STAT3/NF-κB signaling pathway, which may be a potent target for psoriasis treatment.

In vivo evaluation of the antipsoriatic effect of hydrogel with lavandin essential oil and its main components after topical application

In our study, lavandin oil was hydrodistillated from Lavandula × intermedia (Lamiaceae), and new alginate-based hydrogel formulations containing lavandin oil, linalool, and linalyl acetate were prepared for the first time. Using the gas chromatography (GC) and gas chromatography - mass spectrometry (GC-MS) methods fifty eight components of obtained essential oil were identified. Subsequently, the antipsoriatic activity of the created formulations was investigated by applying an imiquimod-induced mouse model. Alginate-based hydrogels were used as carriers for lavandin oil, linalool, and linalyl acetate. The histopathological examination of imiquimod-induced psoriasis-like mice ear skin stained with H&E (haematoxylin and eosin) was conducted after applying the examined formulations. Additionally, the impact of lavandin oil, linalool, and linalyl acetate on the expression of CD3 (cluster of differentiation 3), CD68 (monoclonal mouse anti-human), and Ki67 (marker of proliferation Ki-67) were studied. Histopathological studies showed that analysed formulations decreased the mice ears’ thickness and the analysed psoriasis symptoms (parakeratosis epidermal thickening, hypertrophy of the spinous layer, inflammatory infiltrates, Munro's microabscesses, Kogoj's micro-pustules, and dermal papillae oedema). The prepared formulations inhibited proliferation of the cells (Ki67 staining method) and expression of CD3 and CD68. The most potent activity against the inflammation in psoriasis was the preparation containing 5% lavandin oil.

A promising impact of oral administration of noscapine against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory autoimmune disease. The effectiveness of noscapine has been employed as a helpful treatment for various disorders and subjected to recent theoretical breakthroughs. Psoriasis-like lesions were induced by topical application of 5% imiquimod (IMQ) (10 mg/cm2 of skin) in male Balb/c mice and then medicated with a single oral dose of methotrexate (MET) as a positive control or daily oral treatment of noscapine (5, 15 and 45 mg/kg). In this way, skin inflammation intensity, psoriatic itchiness, psoriasis area severity index (PASI) score, ear length, thickness, and organ weight were daily measured. At the end of the study, histological and immunohistochemical and enzyme-linked immunosorbent assays (ELISA, for pro-/anti-inflammatory factors) were performed in each ear. IMQ caused psoriasis-like lesions. Noscapine markedly alleviated macroscopic parameters, namely ear thickness, ear length, skin inflammation, itching, and organ weight, as well as microscopic parameters including, pathology and Ki67 and p53, and tissue immunological mediators, such as tumour necrosis factor (TNF-α), interleukin (IL)-10, transforming growth factor (TGF-β), interferon- (IFN-), IL-6, IL-17, and IL-23p19 in the psoriatic skin in a concentration manner (p<0.05-<0.001). Therefore, noscapine with good pharmacological properties has considerable effects on psoriasis inflammation.

The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review.

Accumulating evidence considers psoriasis a systemic inflammatory disorder that is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, and metabolic syndrome. Although the precise pathogenetic links between psoriasis and atherosclerosis warrants further investigation, it is believed that chronic systemic inflammation along with the T helper (Th)-1 and Th17 polarization are associated with endothelial dysfunction and subsequent acceleration of atherosclerosis. Considering the above, several studies have evaluated if optimal control of the inflammation in psoriasis by inhibiting interleukins targeting the Interleukin (IL)-23/Th17 axis could subsequently reduce the atherosclerotic process during anti-psoriatic treatment by using a variety of surrogate markers of subclinical atherosclerosis. This systematic review summarizes current knowledge on the pathogenetic mechanisms and diagnostic evaluation of atherosclerosis in the context of psoriasis and provides a systematic review of the literature on the impact of treatment with biologics targeting the IL-23/Th17 axis on subclinical atherosclerosis in patients with plaque psoriasis and/or psoriatic arthritis.

Comparative studies on mannan and imiquimod induced experimental plaque psoriasis inflammation in inbred mice.

Psoriasis is a genetically determined, environmentally triggered, immune system-mediated autoimmune disease. Different animal models are needed to investigate the complex pathological mechanisms underlying this disease. Therefore, we established mannan-induced psoriasis model and compared with the most commonly used imiquimod-induced psoriasis in terms of disease, induction of innate immune cells, expression of cytokines, and the effect of dexamethasone treatment. Mannan significantly induced more severe psoriasis with better disease relapsing feature than imiquimod (IMQ). As determined by immunohistochemistry, IMQ induced significantly more infiltration of CD11c+ and F4/80+ cells than mannan in the skin. However, cytometric analysis showed a significant increase in the percentage of Gr-1+ neutrophils in the spleen and lymph nodes as well as F4/80+ macrophages in the spleen after mannan exposure. Variation in the percentage of significantly increased Vγ4 T cells was also found to be dependent on the lymphoid organs tested. However, there is a clear difference between these models in terms of expression of certain cytokine genes: IL-22, IL-23, IL-17E, and IL-17F were expressed more predominantly in mannan-induced inflammation, while IL-6 and IL-17A expressions were significantly higher in IMQ model. Interestingly, dexamethasone treatment strongly reduced epidermal thickness and histological scores induced by mannan than IMQ. Despite inducing psoriasis-like inflammation, certain differences and similarities were observed in the immune responses induced by mannan and IMQ. However, mannan-induced psoriasis model is relatively more simple, economical and less harmful to mice with an increased possibility to develop a chronic psoriasis model by exposing mice to mannan.

The Relationship of Depression and Systemic Inflammation in Psoriasis: Findings from the UK Biobank

Psoriasis is regarded as a systemic inflammatory disease, however the significance of inflammatory burden for psychiatric comorbidity is not clear (Griffiths et al., 2017). A bidirectional association between psoriasis and depression is observed, negatively affecting patients’ disability, psoriasis course and psoriatic arthritis (PsA) risk (Lewinson et al., 2017). Mounting evidence of low-grade systemic inflammation in physically healthy depressed individuals led to the hypothesis that immunological processes may drive the psoriasis-depression comorbidity (Griffiths et al., 2017).

Early intervention in psoriasis: Where do we go from here?

Patients with psoriasis often have comorbidities and are at increased risk of developing several complications compared with the general population. Knowledge on the role of immune mediators and systemic inflammation in psoriasis has led to the hypothesis that early intervention with systemic therapy has the potential to modify the course of the disease and reduce the risk of long-term adverse outcomes. In this article, we address some potential issues that need to be considered before early intervention can be implemented routinely. The first is determining what constitutes "early" intervention for psoriasis. A second point is whether the intervention should be considered for patients with early disease or for selected subsets based on risk stratification. A third important consideration is defining success for early intervention. Finally, adoption of early and effective intervention should be based on high-level evidence. Ideally, randomized trials would be the best strategy to compare early vs. late systemic treatment in patients with psoriasis, probably using the frequency of long-term outcomes as primary endpoint, with cutaneous and pharmacoeconomic outcomes assessed secondarily.

Positive correlation of psoriasis vulgaris severity and HOMA-IR

Background: Psoriasis vulgaris is a chronic inflammatory skin disease that its aetiology is still not completely known. A chronic inflammation in psoriasis can cause organ dysfunctions. Elevation of proinflammatory cytokines gives rise to insulin resistance by inhibiting insulin and glucose transport mechanism signals. Insulin resistance is the underlying pathogenesis of metabolic syndrome.&#x0D; Objective: This study aimed to undestand any correlation in the severity of psoriasis vulgaris with HOMA-IR.&#x0D; Methods: A cross sectional research involving 35 subjects with psoriasis vulgaris and 15 subjects without who met the selection criteria. HOMA-IR is a formula used to measure insulin resistance which calculates the fasting insulin value in μU/ml x fasting glucose in mg/DL/405 taken from the blood veins of subjects. PASI score was used to determine psoriasis vulgaris severity.&#x0D; Results: This study shows that the HOMA-IR median value was higher in psoriasis subject than the subjects without psoriasis (p&lt;0.05). The correlaton analysis shows a moderate positive correlation between psoriasis vulgaris severity and HOMA-IR (r= 0.427; p&lt;0.05). The prevalence ratio was 8.57, which means psoriasis vulgaris subjects were 8.57 times more likely to have HOMA-IR compared to those without psoriasis vulgaris (p&lt;0.05; 95%CI: 1.26-58.1).&#x0D; Conclusion: This study concludes that there is a moderate positive correlation between severity of psoriasis vulgaris and HOMA-IR values.