Dataset Information

The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis.

ABSTRACT: Inflammasome activation in the innate immune response plays a role in the pathogenesis of psoriasis largely due to the increased levels of pro-inflammatory cytokines. However, the precise role of inflammasomes in psoriasis (Ps) and psoriatic arthritis (PsA) is largely undefined. To establish the reliability of inflammasome signaling proteins as diagnostics and predictive biomarkers of clinical severity in this disease population, serum from healthy donors and patients with Ps/PsA were analyzed for the protein expression of caspase-1, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), interleukin (IL)-1? and IL-18 levels to determine cut-off points, positive and negative predictive values, and receiver operator characteristic (ROC) curves. Our data revealed that ASC and IL-18 proteins were significantly higher in the Ps group when compared to healthy controls. The area under the curve (AUC) for ASC was 0.9224 with a cut-off point of 321.8 pg/ml, while IL-18 had an AUC of 0.7818 and a cut-off point of 232.1 pg/ml. In addition, levels of IL-18 had a statistically significant linear correlation with that of ASC with an adjusted R squared of 0.2566, indicating that approximately 25% of IL-18 levels could be explained by ASC levels in serum. Our findings indicate that ASC and IL-18 play a significant role in the inflammatory response associated with the pathology of Ps. These inflammasome proteins appear to be key biomarkers in determining diagnoses in this patient population.

SUBMITTER: Forouzandeh M

PROVIDER: S-EPMC7438850 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis.

Forouzandeh Mahtab M Besen Jaren J Keane Robert W RW de Rivero Vaccari Juan Pablo JP

Frontiers in pharmacology 20200811

Inflammasome activation in the innate immune response plays a role in the pathogenesis of psoriasis largely due to the increased levels of pro-inflammatory cytokines. However, the precise role of inflammasomes in psoriasis (Ps) and psoriatic arthritis (PsA) is largely undefined. To establish the reliability of inflammasome signaling proteins as diagnostics and predictive biomarkers of clinical severity in this disease population, serum from healthy donors and patients with Ps/PsA were analyzed f ...[more]

PMID: 32903782

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Project description:Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10-7) including upregulation of CASP5 and interleukin ( IL) -1β. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β ( Z score 3.7; P=1.02×10-23) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.

Project description:Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1β. IL-1β production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1β in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-α, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased caspase-1 activity and IL-1β protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-α, MCP-1, and attenuated alcohol-induced IL-1β increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up-regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC-deficient mice were protected from caspase-1 activation and alcohol-induced IL-1β increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1β, TNF-α, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1β administration induced TNF-α and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase-1 activation and IL-1β increase in the cerebellum. IL-1β amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol-induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation.

Dataset Information

The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis.

Publications

The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis.

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