Publications of Souad Rahmouni
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See detailSequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility
International IBD Genetics Consortium; Rahmouni, Souad ULiege; Georges, Michel ULiege

in MedRxiv (2022)

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding ... [more ▼]

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time. [less ▲]

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See detailThe genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage following ischemia/reperfusion injury in mouse
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Acta Physiologica (2021)

Aim: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ... [more ▼]

Aim: Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ischemia/reperfusion (I/R). We postulate that the functional loss of DUSP3 is associated with kidney resistance to I/R. Methods: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal I/R (30min/48h). Renal injury was assessed based on serum levels of urea (BUN) and Jablonski score. The expression of CD31 and VEGF vascular markers was quantified by RT-qPCR and immuno-staining. Renal resistivity index (RRI) was measured in vivo by Doppler ultrasound. Comparative phosphoproteomics was conducted using IMAC enrichment of phosphopeptides. Inflammatory markers were quantified at both mRNA and protein levels in ischemic vs. non-ischemic kidneys in WT versus Dusp3-/- . Results: At baseline, we located DUSP3 in renal glomeruli and endothelial cells. CD31-positive vascular network was significantly larger in Dusp3-/- kidneys compared to WT, with a lower RRI in Dusp3-/- mice. Following I/R, BUN and Jablonski score were significantly lower in Dusp3-/- vs. WT mice. Phosphoproteomics highlighted a down-regulation of inflammatory pathways and up-regulation of phospho-sites involved in cell metabolism and VEGF-related angiogenesis in Dusp3-/- vs. WT ischemic kidneys. Dusp3-/- ischemic kidneys showed decreased mRNA levels of CD11b, TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b-positive cells were reduced in Dusp3-/- vs. WT kidneys post I/R. Conclusion: Genetic inactivation of Dusp3 is associated with kidney conditioning against I/R, possibly due to attenuated inflammation and improved perfusion. [less ▲]

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See detailAge-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.
Nakanishi, Tomoko; Pigazzini, Sara; Degenhardt, Frauke et al

in Journal of Clinical Investigation (2021), Online ahead of print.

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the ... [more ▼]

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. METHOD: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FINDINGS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. INTERPRETATION: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FUNDING: Funding was obtained by each of the participating cohorts individually. [less ▲]

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See detailRole of the Dual Specificity Phosphatase 3 (DUSP3) in renal ischemia/reperfusion injury
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2021, August 31)

● Background: DUSP3 is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. We study (i) whether and where DUSP3 is expressed in the renal ... [more ▼]

● Background: DUSP3 is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. We study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in mice (Dusp3-/-) attenuates the ischemic injury. ● Methods: Exp1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia(30min)/reperfusion(48h) (I/R). Renal function was assessed upon I/R biomarkers: serum levels of urea (BUN) and creatinine (SCr). The expression of inflammatory markers was quantified at both mRNA and protein levels in ischemic vs. non-ischemic kidneys in WT vs Dusp3-/-. Exp2: Renal resistivity index (RRI) was measured by Doppler ultrasound (n=10 mice). The expression of CD31 and VEGF vascular markers was quantified by qPCR and immuno-staining. ● Results: Exp1: An immuno-reactive signal for DUSP3 was detected in nephrin-positive glomeruli and in Meca-32-positive endothelial cells in both outer and inner medulla, with no immunoreactivity in Dusp3-/- kidneys. Following I/R, the mRNA level of DUSP3 was increased 1.8-fold compared to baseline. Immunoblotting showed a 77-fold increased expression of DUSP3 post I/R. Serum levels of I/R biomarkers were significantly lower in Dusp3-/- compared to WT mice following renal I/R (BUN: 78.4±33.7 vs. 258.9±162.9mg/dL; SCr: 0.1±0.07 vs. 0.8±0.9 mg/dL; p<0.01). At mRNA levels, Dusp3-/- ischemic kidneys showed a significantly decreased expression level of TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to WT. PCNA-, F4-80- and CD11b-positive cells were significantly reduced in Dusp3-/- vs WT renal parenchyma post I/R. Exp2: The RRI was lower in Dusp3-/- compared to WT (0.56±0.03 vs. 0.66±0.02; p<0.001). The Dusp3-/- kidneys were characterized by a 1.8-fold increase of CD31 compared to WT. At mRNA levels, the Dusp3-/- kidneys showed increased basal levels of CD31 and VEGF compared to WT. ● Conclusions: The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury. [less ▲]

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See detailThe genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage following ischemia/reperfusion injury in mouse
Khbouz, Badr ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2021, June 05)

BACKGROUND AND AIMS: Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i ... [more ▼]

BACKGROUND AND AIMS: Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in Dusp3 systemic knock-out (Dusp3-/-) mice attenuates the I/R-associated inflammation and injury. METHOD: Experiment 1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia for 30 minutes followed by a reperfusion of 48 hours. Blood and kidneys were collected. Renal function was assessed upon I/R biomarkers, i.e. blood urea nitrogen (BUN) and creatinine (SCr). Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immuno-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in Dusp3 WT vs. KO mice. Experiment 2: Ten C57BL/6 male WT and Dusp3-/- mice were anesthetized. Renal Doppler ultrasound was performed to assess the renal resistivity index (RRI). The expression of CD31 and VEGF vascular markers was quantified by the means of real time qPCR and and immuno-staining (FiJi software). RESULTS: Experiment 1: An immuno-reactive signal for DUSP3 was detected in the glomeruli (in co-localization with nephrin) and in Meca-32-positive endothelial cells of both outer and inner medulla of mouse non-ischemic WT kidneys. No significant immunoreactivity for DUSP3 was detected in Dusp3-/- kidneys. Following renal I/R, the mRNA level of Dusp3 was increased 1.8-fold compared to baseline (p<0.001). Immunoblot quantifications showed a 77-fold increased expression of DUSP3 post renal I/R. Serum levels of I/R biomarkers were significantly lower in Dusp3-/- compared to WT mice following renal I/R (BUN: 78.4633.7 vs. 258.96162.9mg/dL; SCr: 0.160.07 vs. 0.860.9 mg/dL; p<0.01). At mRNA levels, Dusp3-/- ischemic kidneys showed a significantly decreased expression level of CD11b, TNF-a, KIM-1, IL-6, IL-1b and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b positive cells were significantly reduced in Dusp3-/- vs WT renal parenchyma post I/R. Experiment 2: The RRI non-invasively measured by ultrasound was lower in Dusp3-/- group compared to controls (0.566 0.03 vs. 0.6660.02; p<0.001). The Dusp3-/- non ischemic kidneys were characterized by a 1.8-fold increased surface of CD31-positive cells compared to WT kidneys (p<0.001). At mRNA levels, the Dusp3-/- kidneys showed significantly increased basal levels of CD31 and VEGF compared to controls. CONCLUSION: The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury. [less ▲]

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See detailIdentification of novel loci associated with human microbiota composition
Latour, Samuel ULiege; Shagam, Lev ULiege; Mariman, Rob ULiege et al

Poster (2021, June)

Our understanding of the factors shaping intestinal microbiome composition has increased significantly during last decade. Host genetics is one of these factors and may explain ~10% of the microbiome ... [more ▼]

Our understanding of the factors shaping intestinal microbiome composition has increased significantly during last decade. Host genetics is one of these factors and may explain ~10% of the microbiome variance . So far, and despite the number of GWAS studies performed to identify loci associated with microbiome composition, only few associations were cross‑replicated. This study makes use of an extensive dataset integrating 300 healthy individuals (CEDAR-1 cohort) from whom we obtained (i) genotype (Illumina Human OmniExpress BeadChip imputed to 6M SNPs with MAF⩾5%) (ii) 16S rRNA based taxonomic assignation for biopsies from the ileum, transverse colon and rectum (3 amplicons mapped to SILVA database). We performed a GWAS (PLINK additive model) to unravel new associations between genotype and microbiota. Our findings were further verified in two confirmation cohorts obtained from residual stool samples collected during colonoscopy (n=295), from ileum, transverse colon and rectum biopsies and stools (CEDAR-2 cohort) (n~ 50 and 20) where we also tested for individual variation regarding sample provenance. We observed that intestinal location explained a small part of the microbiome variability (<1%) in our dataset. The variation in microbial composition explained by the individual effect represents the major fraction (>50%). We identified three association between SNP and bacterium abundance at the experiment-wide p-value threshold (6x10-10). Among these three associations, the second and third were reproduced at nominal p value of 5% in the confirmation cohort. We have identified 2 putative novel loci associated with human microbiome composition . We also showed a strong individual effect on bacterial communities and a low location variability across the intestinal tract. [less ▲]

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See detailIn-Depth Longitudinal Comparison of Clinical Specimens to Detect SARS-CoV-2.
Defêche, Justine ULiege; AZARZAR, Samira ULiege; Mesdagh, Alyssia ULiege et al

in Pathogens (Basel, Switzerland) (2021), 10(11),

The testing and isolation of patients with coronavirus disease 2019 (COVID-19) are indispensable tools to control the ongoing COVID-19 pandemic. PCR tests are considered the "gold standard" of COVID-19 ... [more ▼]

The testing and isolation of patients with coronavirus disease 2019 (COVID-19) are indispensable tools to control the ongoing COVID-19 pandemic. PCR tests are considered the "gold standard" of COVID-19 testing and mostly involve testing nasopharyngeal swab specimens. Our study aimed to compare the sensitivity of tests for various sample specimens. Seventy-five participants with confirmed COVID-19 were included in the study. Nasopharyngeal swabs, oropharyngeal swabs, Oracol-collected saliva, throat washes and rectal specimens were collected along with pooled swabs. Participants were asked to complete a questionnaire to correlate specific clinical symptoms and the symptom duration with the sensitivity of detecting COVID-19 in various sample specimens. Sampling was repeated after 7 to 10 days (T2), then after 14 to 20 days (T3) to perform a longitudinal analysis of sample specimen sensitivity. At the first time point, the highest percentages of SARS-CoV-2-positive samples were observed for nasopharyngeal samples (84.3%), while 74%, 68.2%, 58.8% and 3.5% of throat washing, Oracol-collected saliva, oropharyngeal and rectal samples tested positive, respectively. The sensitivity of all sampling methods except throat wash samples decreased rapidly at later time points compared to the first collection. The throat washing method exhibited better performance than the gold standard nasopharyngeal swab at the second and third time points after the first positive test date. Nasopharyngeal swabs were the most sensitive specimens for early detection after symptom onset. Throat washing is a sensitive alternative method. It was found that SARS-CoV-2 persists longer in the throat and saliva than in the nasopharynx. [less ▲]

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See detailDual‑specificity phosphatase 3 deletion promotes obesity, non‑alcoholic steatohepatitis and hepatocellular carcinoma
Jacques, Sophie ULiege; Arjomand, Arash ULiege; Perée, Hélène ULiege et al

in Scientific Reports (2021), 11

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and ... [more ▼]

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage. [less ▲]

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See detailNew approach to determine the healthy immune variations by combining clustering methods
Lieferinckx, Claire; De Grève, Zacharie; Toubeau, Jean‑François et al

in Scientific Reports (2021), 11

Immune-mediated infammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defning the limits of a healthy immune system is therefore ... [more ▼]

Immune-mediated infammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defning the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their infuencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefcients of variation confrmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors afected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some infuence of age, gender, BMI, cortisol, season and CMV infection on immune variability [less ▲]

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See detailIdentification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR
Scherer, Michael; Gasparoni, Gilles; Rahmouni, Souad ULiege et al

in Epigenetics and Chromatin (2021), 14(1), 44

Background: Understanding the influence of genetic variantson DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches ... [more ▼]

Background: Understanding the influence of genetic variantson DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL) but also for discriminating general from cell-type-specific effects. Results: Here, we present a two-step computational framework MAGAR, which fully supports identification of methQTLs from matched genotyping and DNA methylation data, and additionally the identification of quantitative cell-type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T-cells, B-cells) from healthy individuals and demonstrate the discrimination of common from cell-type-specific methQTLs. We experimentally validate both types of methQTLs in an independent dataset comprising additional cell types and tissues. Finally, we validate selected methQTLs (PON1, ZNF155, NRG2) by ultra-deep local sequencing. In line with previous reports, we find cell-type-specific methQTLs to be preferentially located in enhancer elements. Conclusions: Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell-type-specific epigenomic variation. [less ▲]

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See detailMapping the human genetic architecture of COVID-19 by worldwide meta-analysis
The COVID-19 Host Genetics Initiative; Gazon, Hélène; JUSZCZAK, Danusia ULiege et al

in Nature (2021)

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 ... [more ▼]

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 15 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. We further identified smoking and body mass index as causal risk factors for severe COVID-19. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. This working model of international collaboration a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease. [less ▲]

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See detailCRELD1 modulates homeostasis of the immune system in mice and humans
Bonaguro, Lorenzo; Köhne, Maren; Schmidleithner, Jonas et al

in Nature Immunology (2020), 12

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting ... [more ▼]

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis. [less ▲]

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See detailMultiomics Analyses to Deliver the Most Effective Treatment to Every Patient With Inflammatory Bowel Disease.
Weersma, RK; Barrett, JC; Vermeire, S et al

in Gastroenterology (2018), 155(5), 1-4

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See detailGenetic deletion of DUSP3 phosphatase attenuates kidney damage and inflammation following ischemia/reperfusion in mouse
Rowart, Pascal ULiege; POMA, Laurence ULiege; Rahmouni, Souad ULiege et al

Poster (2018, May 25)

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly ... [more ▼]

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly expressed in endothelial cells, as well as in platelets, monocytes and macrophages. Since DUSP3 is a positive regulator of the innate immune response, its inactivation/deletion may attenuate kidney inflammation and damage caused by I/R. Methods. Ten-weeks-old C57BL/6 wild-type (WT, n=10) versus systemic knock-out (KO, n=10) mice underwent unilateral left renal ischemia for 30 minutes. Right nephrectomy was simultaneously performed. The left kidney was excised and blood sample was collected from inferior vena cava at 48h post reperfusion. Renal function was assessed upon Blood Urea Nitrogen (BUN) levels. Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immune-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in DUSP3 WT vs. KO mice. Results. BUN reached 259±51 vs 78±11mg/dL in WT and KO, respectively (p<0.01). DUSP3 KO ischemic kidneys showed a reduced number of PCNA- (3-fold, p<0.001), CD11b- (3.5-fold, p<0.001) and F4-80-positive cells (1.7-fold, p<0.001) in comparison to WT. The expression levels of CD11b (2.2-fold, p<0.01), HSP70 (2.7-fold, p<0.01) and PCNA (10-fold, p<0.001) were significantly decreased in DUSP3 KO compared to WT ischemic kidneys. By contrast, a 1.5-fold increase of anti-inflammatory M2 CD206-positive macrophages was observed in DUSP3 KO ischemic kidneys. At transcriptional levels, DUSP3 WT vs. KO ischemic kidneys (normalized to WT sham-operated right kidneys) showed an upregulation of 6.5-fold (p<0.05) vs. 10.5-fold (p<0.01) of M2-type macrophage (Arginase), 4.6-fold (p<0.001) vs. 2.2-fold (p<0.05) of CD11b, 4.5-fold (p<0.001) vs. 0.7-fold (p>0.05) of TNF and 111-fold (p<0.001) vs. 4.5-fold (p>0.05) of KIM-1, respectively. Conclusions. Genetic deletion of DUSP3 attenuates renal I/R-associated damage and inflammation. [less ▲]

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See detailGenetic deletion of DUSP3 phosphatase attenuates kidney damage and inflammation following ischemia/reperfusion in mouse
Rowart, Pascal ULiege; POMA, Laurence ULiege; Rahmouni, Souad ULiege et al

Conference (2018, April 20)

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly ... [more ▼]

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly expressed in endothelial cells, as well as in platelets, monocytes and macrophages. Since DUSP3 is a positive regulator of the innate immune response, its inactivation/deletion may attenuate kidney inflammation and damage caused by I/R. Methods. Ten-weeks-old C57BL/6 wild-type (WT, n=10) versus systemic knock-out (KO, n=10) mice underwent unilateral left renal ischemia for 30 minutes. Right nephrectomy was simultaneously performed. The left kidney was excised and blood sample was collected from inferior vena cava at 48h post reperfusion. Renal function was assessed upon Blood Urea Nitrogen (BUN) levels. Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immune-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in DUSP3 WT vs. KO mice. Results. BUN reached 259±51 vs 78±11mg/dL in WT and KO, respectively (p<0.01). DUSP3 KO ischemic kidneys showed a reduced number of PCNA- (3-fold, p<0.001), CD11b- (3.5-fold, p<0.001) and F4-80-positive cells (1.7-fold, p<0.001) in comparison to WT. The expression levels of CD11b (2.2-fold, p<0.01), HSP70 (2.7-fold, p<0.01) and PCNA (10-fold, p<0.001) were significantly decreased in DUSP3 KO compared to WT ischemic kidneys. By contrast, a 1.5-fold increase of anti-inflammatory M2 CD206-positive macrophages was observed in DUSP3 KO ischemic kidneys. At transcriptional levels, DUSP3 WT vs. KO ischemic kidneys (normalized to WT sham-operated right kidneys) showed an upregulation of 6.5-fold (p<0.05) vs. 10.5-fold (p<0.01) of M2-type macrophage (Arginase), 4.6-fold (p<0.001) vs. 2.2-fold (p<0.05) of CD11b, 4.5-fold (p<0.001) vs. 0.7-fold (p>0.05) of TNF and 111-fold (p<0.001) vs. 4.5-fold (p>0.05) of KIM-1, respectively. Conclusions. Genetic deletion of DUSP3 attenuates renal I/R-associated damage and inflammation. [less ▲]

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See detailGenetic deletion of DUSP3 phosphatase attenuates kidney damage and inflammation following ischemia/reperfusion in mouse
Rowart, Pascal ULiege; POMA, Laurence ULiege; Rahmouni, Souad ULiege et al

Conference (2018, March 16)

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly ... [more ▼]

Background. Renal ischemia-reperfusion (I/R) injury represents an unavoidable event in kidney transplantation. Dual Specificity Phosphatase 3 (DUSP3, also called Vaccinia-H1 Related (VHR)) is highly expressed in endothelial cells, as well as in platelets, monocytes and macrophages. Since DUSP3 is a positive regulator of the innate immune response, its inactivation/deletion may attenuate kidney inflammation and damage caused by I/R. Methods. Ten-weeks-old C57BL/6 wild-type (WT, n=10) versus systemic knock-out (KO, n=10) mice underwent unilateral left renal ischemia for 30 minutes. Right nephrectomy was simultaneously performed. The left kidney was excised and blood sample was collected from inferior vena cava at 48h post reperfusion. Renal function was assessed upon Blood Urea Nitrogen (BUN) levels. Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immune-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in DUSP3 WT vs. KO mice. Results. BUN reached 259±51 vs 78±11mg/dL in WT and KO, respectively (p<0.01). DUSP3 KO ischemic kidneys showed a reduced number of PCNA- (3-fold, p<0.001), CD11b- (3.5-fold, p<0.001) and F4-80-positive cells (1.7-fold, p<0.001) in comparison to WT. The expression levels of CD11b (2.2-fold, p<0.01), HSP70 (2.7-fold, p<0.01) and PCNA (10-fold, p<0.001) were significantly decreased in DUSP3 KO compared to WT ischemic kidneys. By contrast, a 1.5-fold increase of anti-inflammatory M2 CD206-positive macrophages was observed in DUSP3 KO ischemic kidneys. At transcriptional levels, DUSP3 WT vs. KO ischemic kidneys (normalized to WT sham-operated right kidneys) showed an upregulation of 6.5-fold (p<0.05) vs. 10.5-fold (p<0.01) of M2-type macrophage (Arginase), 4.6-fold (p<0.001) vs. 2.2-fold (p<0.05) of CD11b, 4.5-fold (p<0.001) vs. 0.7-fold (p>0.05) of TNF and 111-fold (p<0.001) vs. 4.5-fold (p>0.05) of KIM-1, respectively. Conclusions. Genetic deletion of DUSP3 attenuates renal I/R-associated damage and inflammation. [less ▲]

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See detailPlatelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression
Servais, Laurence ULiege; Wéra, Odile ULiege; Dibato Epoh, John et al

in Journal of Thrombosis and Haemostasis (2018)

Background: Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, though the mechanisms are not fully understood. Beyond thrombosis and hemostasis ... [more ▼]

Background: Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, though the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors of inflammation; they also have been involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective: To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods: We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and their reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at pre-tumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results: At pre-tumoral stage, hyperactive platelets were a major source of circulating pro-tumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of plasma SAA, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells as well as their infiltration in tumors, while tissue CD8 T cells were augmented. Platelets or releasates of platelets from cancer mice both were able to polarize myeloid cells toward an immunosuppressive phenotype. Conclusions: Thus, platelets promote initiation of colitis-associated cancer by enhancing myeloid cell dependent immunosuppression. Antiplatelet agents may help prevent inflammation-elicited carcinogenesis by restoring antitumor immunity. [less ▲]

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See detailIBD risk loci are enriched in multigenic regulatory modules encompassing causative genes
Yukihide, Momozawa; Dmitrieva, Joelia Borisovna ULiege; Theatre, Emilie ULiege et al

in Nature Communications (2018)

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that ... [more ▼]

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome dataset (9 disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9,720 regulatory modules, of which ∼3,000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that are driveing the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. We resequence 45 of the corresponding 100 candidate genes in 6,600 Crohn disease (CD) cases and 5,500 controls and show that they are significantly enriched in causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using standard burden tests. [less ▲]

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