Generalized Pustular psoriasis (GPP), a rare and potentially life‐threatening auto‐inflammatory disease, is associated with IL36RN mutations. Here, we analyse the prevalence of IL36RN mutations in ...our multi‐ethnic GPP cohort and assess differences in the clinical profile of patients with (IL36RN‐positive) and without (IL36RN‐negative) mutations. IL36RN mutations were present in 17.7% of 137 GPP patients (29.7% of Chinese cases, 17.3% of Malay cases, but 0% of Indian patients). 92% of these individuals carried the c.115 + 6 T > C mutation. Male: female ratio was 1:2.3. Females predominate in both groups with no significant difference between IL36RN‐positive and IL36RN‐negative individuals. The overall mean age (±SD) at disease onset for GPP was 37.6 ± 17.2 years, but disease onset was significantly earlier in IL36RN‐positive vs IL36RN‐negative cases (mean age:30.6 ± 18.92 vs. 39.2 ± 16.49 years, p = 0.027). IL36RN‐positive patients were less likely to have associated plaque psoriasis (52.4% vs. 83.5%, p‐value = 0.002). There was no difference in the common clinical and laboratory manifestations or triggers of GPP between IL36RN‐positive and ‐negative patients, except for geographic tongue which was significantly more common in IL36RN‐positive patients (41.7% vs. 11.9%, p‐value = 0.002). Annual flare rate was significantly higher in IL36RN‐positive compared to IL36RN‐negative (mean ± SD of 1.92 ± 1.32 vs. 1.46 ± 0.90, p = 0.041) cases. However, no significant difference in the rate of hospitalization and length of hospital stay was observed between the two groups. These observations demonstrate that IL36RN disease alleles occur with varying frequencies among Asian populations and are associated with a severe, early‐onset clinical phenotype.
The polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic ...low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to down regulate NF-κB; an important contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the effects.
The study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting.
Imiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways. Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis.
Resveratrol ameliorates psoriasis, and changes expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner, which suggests resveratrol, might have a role in the treatment of psoriasis and should be explored further in a human setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified ...to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.
•First study on the therapeutic effect of Orientin on psoriasis.•Orientin alleviated psoriasis by inhibiting inflammatory response and cell proliferation.•Orientin alleviated psoriasis by inhibiting ...activation of the MAPK pathway.
Psoriasis, a chronic inflammatory condition of the skin, is characterized by an atypical proliferation of epidermal keratinocytes and immune cell infiltration. Orientin is a flavonoid monomer with potent anti-inflammatory activities. However, the therapeutic effects of orientin on psoriasis and the underlying mechanisms have not been elucidated.
To investigate the therapeutic effect of orientin on psoriasis and the underlying mechanisms using network pharmacology and experimental studies.
A psoriasis-like mouse model was established using imiquimod (IMQ). Lipopolysaccharide (LPS) was used to stimulate the RAW264.7 and HaCaT cells in vitro. The therapeutic effects of orientin and the underlying mechanism were analyzed using histopathological, immunohistochemical, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, flow cytometry, and western blotting analyses.
Orientin ameliorated skin lesions and suppressed keratinocyte proliferation and immune cell infiltration in the IMQ-induced psoriasis-like mouse model. Additionally, orientin inhibited the secretion of the pro-inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-8, IL-17, and IL-23 in the psoriasis-like mouse model and LPS-induced RAW264.7 and HaCaT cells. Furthermore, orientin mitigated the LPS-induced upregulation of reactive oxygen species and downregulation of IL-10 and glutathione levels. Orientin alleviated inflammation by downregulating the MAPK signaling pathway.
Orientin alleviated psoriasis-like dermatitis by suppressing the MAPK signaling pathway, suggesting that orientin is a potential therapeutic for psoriasis.
Psoriasis has an enormous impact on patients' lives and is frequently associated with depression. Depression in psoriasis may be attributed, at least in part, to elevated proinflammatory cytokines ...rather than the psychosocial impact of psoriasis itself. Biologics that target inflammatory cytokines treat the clinical manifestations of psoriasis, but may also play a role in reducing associated depression. Multiple biologics have decreased symptoms of depression during clinical trials in psoriasis; however, these studies used a variety of depression screening tools, which limits comparison. Furthermore, it is difficult to distinguish whether improved depression is the result of the direct anti-inflammatory effect of the biologic, or the indirect effect of improved psoriasis leading to better psychological status. Future studies evaluating depression in patients with psoriasis could benefit from a standardized depression screening tool to mitigate discrepancies and facilitate comparison across treatment types. Here, we highlight the inflammatory overlap between psoriasis and depression by examining the pathophysiology of depression, and reviewing psoriasis clinical studies that assessed depression as an outcome measure.
Microorganisms have been implicated in the pathogenesis of psoriasis. Previous studies of psoriasis and normal skin have used swabs from the surface rather than skin biopsies. In this study, biopsies ...were taken from 10 patients with psoriasis and 12 control subjects from unmatched sites. Samples were analysed with massive parallel pyrosequencing on the 454 platform targeting the 16S rRNA gene and the variable regions V3–V4. The samples grouped into 19 phyla, 265 taxon and 652 operational units (OTUs) at 97% identity. A cut-off abundance level was set at 1%. The three most common phyla in both normal and psoriasis skin were Firmicutes (39% psoriasis, 43% normal skin), Proteobacteria (38% psoriasis, 27% normal skin) and Actinobacteria (5% psoriasis, 16% normal skin,
p
= 0.034). In trunk skin, Proteobacteria were present at significantly higher levels in psoriasis compared to controls (52 vs. 32%,
p
= 0.0113). The commonest genera were
Streptococci
in both psoriasis (32%) and normal skin (26%).
Staphylococci
were less common in psoriasis (5%) than in controls (16%), as were
Propionibacteria
(psoriasis 0.0001669%, controls 0.0254%). Both
Staphylococci
and
Propionibacteria
were significantly lower in psoriasis versus control limb skin (
p
= 0.051, 0.046, respectively). This study has shown some differences in microbiota between psoriasis and normal skin. Whether these are of primary aetiological significance, or secondary to the altered skin of psoriasis remains to be determined.
Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. ...Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum.
The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway ...that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis.
A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.
The risk of infection among patients with psoriasis of varying severity in a broadly representative population remains poorly understood. Using The Health Improvement Network (THIN), an electronic ...medical records database representative of the general UK population, we performed a cohort study to determine the risks of serious infection, opportunistic infection, and herpes zoster among patients with versus without psoriasis and according to psoriasis severity. We identified 187,258 patients with mild and 12,442 patients with moderate to severe psoriasis based on treatment patterns. Using Cox proportional hazards regression, the adjusted hazard ratios (95% confidence intervals) for serious infection were 1.18 (1.16–1.21) and 1.63 (1.52–1.75) for the mild and moderate to severe psoriasis groups, respectively. Among a nested cohort of 8,569 psoriasis patients with disease severity classified by body surface area involvement, similar results were obtained with the exception of an attenuated but significantly increased risk of serious infection among the moderate to severe psoriasis group (1.27 1.10–1.47). Overall, the risks of opportunistic infection and herpes zoster were significantly increased only among the moderate to severe psoriasis group and were associated with immunosuppressive therapy. Our analyses suggest that psoriasis is associated with an increased risk of serious infection, and psoriasis severity is a predictor of serious infection risk.
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