Genetic contribution and functional impairment of inflammasome in sickle cell disease

Dutra, Valéria de Freitas; Leal, Vinícius Nunes Cordeiro; Fernandes, Fernanda Pereira; Souza, Cláudia Regina Lustosa; Figueiredo, Maria Stella; Pontillo, Alessandra

doi:10.1016/j.cyto.2021.155717

Cited by 4 publications

(1 citation statement)

References 63 publications

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“…Growing evidence in both patients with SCD and cell/animal-based models of SCD support the importance of NLRP3 inflammasome activation in the severity of the clinical manifestations of SCD as well as in monocyte and platelet function/activation. [42][43][44] Although the mechanism of activation of NLRP3 in SCD is still under investigation, oxidation and free heme/hemolysis have been suggested to trigger the NLRP3 inflammasome in SCD. 45,46 In this model, epeleuton reduces both oxidation and hemolysis when SCD mice are exposed to H/R stress and prevents the worsening of liver iron overload and the activation of the redox-related transcription factor Nrf2.…”

Section: Discussionmentioning

confidence: 99%

Epeleuton, a novel synthetic ω-3 fatty acid, reduces the hypoxia/reperfusion stress in a mouse model of sickle cell disease

Mattè,

Federti,

Recchiuti

et al. 2023

haematol

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Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to SCD disease progression. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response. Epeleuton (15 hydroxy eicosapentaenoic acid ethyl ester) is a novel orally administered second-generation ω-3 fatty acid with a favorable clinical safety profile. In this study we show that epeleuton re-programs the lipidomic pattern of target organs for SCD towards a pro-resolving pattern. This protects against systemic and local inflammatory response and improves red cell features, resulting in reduced hemolysis and sickling compared with vehicle treated SCD mice. In addition, epeleuton prevents the hypoxia/reoxygenation induced activation of NF-kB with downregulation of NLRP3 inflammasome in lung, kidney, and liver. This was associated with down-regulation of vascular activation markers in epeleuton treated SCD mice when compared to vehicle treated animals. Collectively our data support the potential therapeutic utility of epeleuton and provide the rationale for the design of clinical trials to evaluate the efficacy of epeleuton in patients with SCD.

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Section: Discussionmentioning

confidence: 99%

Epeleuton, a novel synthetic ω-3 fatty acid, reduces the hypoxia/reperfusion stress in a mouse model of sickle cell disease

Mattè,

Federti,

Recchiuti

et al. 2023

haematol

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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