Publications of Christophe Desmet
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See detailEosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?
Van Hulst, Glenn ULiege; Bureau, Fabrice ULiege; Desmet, Christophe ULiege

in International journal of molecular sciences (2021), 22(18),

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as ... [more ▼]

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that "not all eosinophils are equal". In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil "endotyping", viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs. [less ▲]

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See detailWobble tRNA modification and hydrophilic amino acid patterns dictate protein fate.
Rapino, Francesca ULiege; ZHOU, ZHAOLI; RONCERO SANCHEZ, Ana Maria et al

in Nature Communications (2021), 12(1), 2170

Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon ... [more ▼]

Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm(5)s(2) wobble uridine tRNA modification (U(34)-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U(34)-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U(34)-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis. [less ▲]

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See detailIdentification of pro-fibrotic macrophage populations by single-cell transcriptomic analysis in West Highland white terriers affected with canine idiopathic pulmonary fibrosis.
Fastrès, Aline ULiege; Pirottin, Dimitri ULiege; Fievez, Laurence ULiege et al

in Frontiers in Immunology (2020), 11

Canine idiopathic pulmonary fibrosis (CIPF) affects old dogs from the West Highland white terrier (WHWT) breed and mimics idiopathic pulmonary fibrosis (IPF) in human. The disease results from deposition ... [more ▼]

Canine idiopathic pulmonary fibrosis (CIPF) affects old dogs from the West Highland white terrier (WHWT) breed and mimics idiopathic pulmonary fibrosis (IPF) in human. The disease results from deposition of fibrotic tissue in the lung parenchyma causing respiratory failure. Recent studies in IPF using single-cell RNA sequencing (scRNA-seq) revealed the presence of profibrotic macrophage populations in the lung, which could be targeted for therapeutic purpose. In dogs, scRNA-seq was recently validated for the detection of cell populations in bronchoalveolar lavage fluid (BALF) from healthy dogs. Here we used the scRNA-seq to characterize disease-related heterogeneity within cell populations of macrophages/monocytes (Ma/Mo) in the BALF from 5 WHWTs affected with CIPF in comparison with 3 healthy WHWTs. Gene set enrichment analysis was also used to assess pro-fibrotic capacities of Ma/Mo populations. Five clusters of Ma/Mo were identified. Gene set enrichment analyses revealed the presence of pro-fibrotic monocytes in higher proportion in CIPF WHWTs than in healthy WHWTs. In addition, monocytes-derived macrophages enriched in pro-fibrotic genes in CIPF compared with healthy WHWTs were also identified. These results suggest the implication of Ma/Mo clusters in CIPF processes, although, further research is needed to understand their role in disease pathogenesis. Overexpressed molecules associated with pulmonary fibrosis processes were also identified that could be used as biomarkers and/or therapeutic targets in the future. [less ▲]

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See detailIdentification of pro-fibrotic macrophages populations by single-cell transcriptomic analysis in West Highland white terriers affected with canine idiopathic pulmonary fibrosis.
Fastrès, Aline ULiege; Pirottin, Dimitri ULiege; Fievez, Laurence ULiege et al

Scientific conference (2020, November 20)

Canine idiopathic pulmonary fibrosis (CIPF) is a not well understand disease which affects old West Highland white terriers (WHWTs) and mimics idiopathic pulmonary fibrosis (IPF) in man. Recent studies in ... [more ▼]

Canine idiopathic pulmonary fibrosis (CIPF) is a not well understand disease which affects old West Highland white terriers (WHWTs) and mimics idiopathic pulmonary fibrosis (IPF) in man. Recent studies in IPF using the single-cell RNA sequencing (scRNA-seq) technique revealed the presence of profibrotic macrophages populations in the lung. Here we used the scRNA-seq to characterize disease-related heterogeneity within cell subsets of macrophages/monocytes (Ma/Mo) in the BALF of 5 WHWTs affected with CIPF in comparison with 3 healthy WHWTs. Five subsets of Ma/Mo were identified. Among them, a monocytes subset present in larger proportion in CIPF WHWTs showed a gene expression profile enriched for pulmonary fibrosis processes (PFPs) (normalized enrichment score (NES) = 1.85, q-value = 0.002). Eight genes associated with PFPs were significantly overexpressed in this subset including CCL2, SPP1, FN1, CCL3, TIMP1, IL1RN, CXCL8 and CCL4. A monocytes-derived macrophages subset enriched for PFPs (NES = 1.87, q-value = 0.007) was also identified with differentially expressed genes between CIPF and healthy WHWTs. Expression in CIPF dogs in this subset was enriched for PFPs (NES = 2.01, q-value = 0.008) with significant overexpression of 4 genes associated with PFPs including FN1, SPP1, CXCL8 and PLAU. ScRNA-seq analysis of BALF specimens from healthy and CIPF WHWTs identified pro-fibrotic Ma/Mo populations enriched in pro-fibrotic genes suggesting the implication of these subpopulations in CIPF processes. Overexpressed molecules were also identified that could be used as biomarkers and/or therapeutic targets in the future. [less ▲]

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See detailCharacterization of the bronchoalveolar lavage fluid by single cell gene expression analysis in healthy dogs: a promising technique.
Fastrès, Aline ULiege; Pirottin, Dimitri ULiege; Fievez, Laurence ULiege et al

in Frontiers in Immunology (2020), 11

Single-cell mRNA-sequencing (scRNA-seq) is a technique which enables unbiased, high throughput and high-resolution transcriptomic analysis of the heterogeneity of cells within a population. This recent ... [more ▼]

Single-cell mRNA-sequencing (scRNA-seq) is a technique which enables unbiased, high throughput and high-resolution transcriptomic analysis of the heterogeneity of cells within a population. This recent technique has been described in humans, mice and other species in various conditions to cluster cells in populations and identify new subpopulations, as well as to study the gene expression of cells in various tissues, conditions and origins. In dogs, a species for which markers of cell populations are often limiting, scRNA-seq presents with elevated yet untested potential for the study of tissue composition. As a proof of principle, we used scRNA-seq to identify cellular populations of the bronchoalveolar lavage fluid (BALF) in healthy dogs (n = 4). A total of 5710 cells were obtained and analyzed by scRNA-seq. Fourteen distinct clusters of cells were identified, further identified as macrophages/monocytes (4 clusters), T cells (2 clusters) and B cells (1 cluster), neutrophils (1 cluster), mast cells (1 cluster), mature or immature dendritic cells (1 cluster each), ciliated or non-ciliated epithelial cells (1 cluster each) and cycling cells (1 cluster). We used for the first time in dogs the scRNA-seq to investigate cellular subpopulations of the BALF of dog. This study hence expands our knowledge on dog lung immune cell populations, paves the way for the investigation at single-cell level of lower respiratory diseases in dogs, and establishes that scRNA-seq is a powerful tool for the study of dog tissue composition. [less ▲]

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See detailThe phosphoinositide 5-phosphatase INPP5K: from gene structure to in vivo functions
Schurmans, Stéphane ULiege; Vande Catsyne, Charles-Andrew ULiege; Desmet, Christophe ULiege et al

in Advances in Biological Regulation (2020)

INPP5K (Inositol Polyphosphate 5-Phosphatase K, or SKIP (for Skeletal muscle and Kidney enriched Inositol Phosphatase) is a member of the phosphoinositide 5-phosphatases family. Its protein structure is ... [more ▼]

INPP5K (Inositol Polyphosphate 5-Phosphatase K, or SKIP (for Skeletal muscle and Kidney enriched Inositol Phosphatase) is a member of the phosphoinositide 5-phosphatases family. Its protein structure is comprised of a N-terminal catalytic domain which hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH domain at the C-terminus which is responsible for protein-protein interactions and subcellular localization of INPP5K. Strikingly, INPP5K is mostly concentrated in the endoplasmic reticulum, although it is also detected at the plasma membrane, in the cytosol and the nucleus. Recently, mutations in INPP5K have been detected in patients with a rare form of autosomal recessive congenital muscular dystrophy with cataract, short stature and intellectual disability. INPP5K functions extend from control of insulin signaling, endoplasmic reticulum stress response and structural integrity, myoblast differentiation, cytoskeleton organization, cell adhesion and migration, renal osmoregulation, to cancer. The goal of this review is thus to summarize and comment recent and less recent data in the literature on INPP5K, in particular on the structure, expression, intracellular localization, interactions and functions of this specific member of the 5-phosphatases family. [less ▲]

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See detailCharacterization of the bronchoalveolar lavage fluid by single cell gene expression analysis in healthy dogs: a promising technique.
Fastrès, Aline ULiege; Pirottin, Dimitri ULiege; Fievez, Laurence ULiege et al

in Journal of Veterinary Internal Medicine (2020), 34(6),

Single‐cell mRNA‐sequencing (scRNA‐seq) is a technique which enables unbiased, high throughput and high‐resolution transcriptomic analysis of the heterogeneity of cells within a population. This recent ... [more ▼]

Single‐cell mRNA‐sequencing (scRNA‐seq) is a technique which enables unbiased, high throughput and high‐resolution transcriptomic analysis of the heterogeneity of cells within a population. This recent technique has been described in humans, mice and other species in various conditions to cluster cells in populations and identify new subpopulations, as well as to study the gene expression of cells in various tissues, conditions and origins. In dogs, a species for which markers of cell populations are often limiting, scRNA‐seq presents with elevated yet untested potential for the study of tissue composition. As a proof of principle, we used scRNA‐seq to identify cellular populations of the bronchoalveolar lavage fluid (BALF) in healthy dogs (n = 4). Cells in suspension isolated from fresh BALF were loaded into the ChromiumTM and were directly encapsulated with unique barcoded primers using the drop‐sequencing method. Cells were lysed and reverse transcription of mRNAs took place into vesicles. cDNA was amplified after the breakage of the vesicles and sequenced on an Illumina NextSeq500. The analysis of the results and statistical analysis were performed using Cell Ranger software (v1.2.0), Seurat package in RStudio (v3.1.2) and the gene set enrichment analysis tool (GSEA‐P). A total of 5710 cells were obtained and analyzed. Fourteen distinct clusters of cells were identified, further identified as alveolar macrophages (AMs) (3 clusters) and monocytes‐derived macrophages (1 cluster). The first cluster of AMs composed by the majority of cells exerted functions involved in immune defense and response, the second cluster exerted functions involved in immune response regulation and the third exerted functions involved in metal ions homeostasis. Clusters of CD8+ and CD4+ T cells were also found (1 cluster each) as well as clusters of mature and immature dendritic cells (1 cluster each) and clusters of ciliated or non‐ciliated epithelial cells (1 cluster each). Finally, subpopulations of B cells, neutrophils, basophils and cycling cells were also identified (1 cluster each). We used for the first time in dogs the scRNA‐seq to investigate cellular subpopulations of the BALF. This study hence expands our knowledge on dog lung immune cell populations, paves the way for the investigation at single‐cell level of lower respiratory diseases in dogs, and establishes that scRNA‐seq is a powerful tool for the study of dog tissue composition. [less ▲]

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See detailGrowth hormone (GH) deficient mice with GHRH ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae
Farhat, Khalil; Bodart, Gwennaëlle ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Immunology (2018), 9

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene ... [more ▼]

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh−/−) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh−/− mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh−/− mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh−/− mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh−/− mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh−/− mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh−/− mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae. [less ▲]

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See detailHuman papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation
Van hede, Dorien ULiege; Polese, Barbara ULiege; Humblet, Chantal ULiege et al

Poster (2018, June)

Background: γδ T cells have been shown to protect against the formation of squamous cell carcinoma (SCC) in several models. Yet, the role of γδ T cells in human papillomavirus (HPV) associated uterine ... [more ▼]

Background: γδ T cells have been shown to protect against the formation of squamous cell carcinoma (SCC) in several models. Yet, the role of γδ T cells in human papillomavirus (HPV) associated uterine cervical SCC, the third cause of death by cancer in women, is unknown. Method: We investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16-oncoproteins. Human uterine cervical biopsies of women infected by HPV were also analyzed. Results: Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16-oncoproteins induced a decrease in epidermal Skint1 expression and the associated anti-tumor Vγ5+ γδ T cells, which were replaced by γδ T cell subsets (mainly Vγ6+ γδlowCCR2+CCR6-) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could be only observed at the cancer stage (SCC), where HPV-oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16-oncoproteins induce a reorganization of the local epithelial-associated γδ T cell subpopulations thereby promoting angiogenesis and cancer development. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailL’expérimentation animale reste indispensable (OPINION)
Amorim, Christiani; Andris, Fabienne; Arckens, Lut et al

Article for general public (2017)

Trop fréquemment, l’expérimentation animale est présentée comme une pratique archaïque. Elle a bien changé. Et 100 % des patients traités le sont grâce aux concepts et techniques développés grâce à elle.

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See detailA surprising and dramatic neuroendocrine-immune phenotype of mice deficient in Growth Hormone-Releasing Hormone (GHRH)
Farhat, Khalil; Bodart, Gwennaëlle ULiege; RENARD, Jeanne de Chantal ULiege et al

Poster (2017, May 23)

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a ... [more ▼]

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a consensus about GH immunomodulatory properties. These studies investigated the immune and anti-infectious response of dwarf Ghrh-/- mice presenting a severe deficiency of the GHRH/GH/IGF-1 axis. In basal conditions, thymic parameters and T-cell responses of Ghrh-/- mice were not severely affected but a constant B-cell lymphopaenia was observed. Thus, we investigated vaccine and anti-infectious responses of Ghrh-/- mice toward Streptococcus pneumonia, a B-dependent pathogen, Ghrh-/- mice were unable to trigger production of specific IgM and IgG against serotype 1 pneumococcal polysaccharide (PPS) after vaccination with either native PPS (Pnx23) or protein-PPS conjugate (Prev-13) vaccines. These vaccines both include the serotype 1 (our S.pneumoniae strain) and provide an effective protection in mice. A short GH supplementation to Ghrh-/- mice (1 daily injection of 1 mg/kg GH for 4 weeks) restored IgM and IgG response to Pnx23 vaccine but not to Prev-13. This suggests that GH could exert distinct impacts upon spenic areas. Furthermore, after intranasal instillation of a non-lethal dose (defined by the full clearance by WT C57BL/6 mice after 24h) of serotype 1 S.pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility. This was proved by a marked time-dependent increase in pulmonary bacterial, a septicemia already 24h after infection and a survival limit of 72h. We also observed a dramatic decrease in lung B- and T-cell populations and an increase in proportion of inflammatory macrophages. By contrast, wild-type and heterozygote mice completely cleared S.pneumoniae infection after 24h. In conclusion, our data show without ambiguity that the somatotrope GHRH/GH/IGF-1 axis plays an important and unsuspected role in defense against S.Pneumoniae. [less ▲]

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See detailA surprising and dramatic neuroendocrine-immune phenotype of mice deficient in Growth Hormone-Releasing Hormone (GHRH)
Farhat, Khalil ULiege; Bodart, Gwennaëlle ULiege; Renard, chantal et al

Poster (2017, May)

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a ... [more ▼]

In the framework of close interactions between the immune and neuroendocrine systems, Growth Hormone (GH) has been proposed to exert significant effects on the immune system, but there is not yet a consensus about GH immunomodulatory properties. These studies investigated the immune and anti-infectious response of dwarf Ghrh-/- mice presenting a severe deficiency of the GHRH/GH/IGF-1 axis. In basal conditions, thymic parameters and T-cell responses of Ghrh-/- mice were not severely affected but a constant B-cell lymphopaenia was observed. Thus, we investigated vaccine and anti-infectious responses of Ghrh-/- mice toward Streptococcus pneumonia, a B-dependent pathogen, Ghrh-/- mice were unable to trigger production of specific IgM and IgG against serotype 1 pneumococcal polysaccharide (PPS) after vaccination with either native PPS (Pnx23) or protein-PPS conjugate (Prev-13) vaccines. These vaccines both include the serotype 1 (our S.pneumoniae strain) and provide an effective protection in mice. A short GH supplementation to Ghrh-/- mice (1 daily injection of 1 mg/kg GH for 4 weeks) restored IgM and IgG response to Pnx23 vaccine but not to Prev-13. This suggests that GH could exert distinct impacts upon spenic areas. Furthermore, after intranasal instillation of a non-lethal dose (defined by the full clearance by WT C57BL/6 mice after 24h) of serotype 1 S.pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility. This was proved by a marked time-dependent increase in pulmonary bacterial, a septicemia already 24h after infection and a survival limit of 72h. We also observed a dramatic decrease in lung B- and T-cell populations and an increase in proportion of inflammatory macrophages. By contrast, wild-type and heterozygote mice completely cleared S.pneumoniae infection after 24h. In conclusion, our data show without ambiguity that the somatotrope GHRH/GH/IGF-1 axis plays an important and unsuspected role in defense against S.Pneumoniae. [less ▲]

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See detailHuman papillomavirus oncoproteins induce a reorganization of epithelial-associated gammadelta T cells promoting tumor formation.
Van hede, Dorien ULiege; Polese, Barbara ULiege; Humblet, Chantal ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114(43), 9056-9065

It has been shown that gammadelta T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of gammadelta T cells in human papillomavirus (HPV)-associated ... [more ▼]

It has been shown that gammadelta T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of gammadelta T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of gammadelta T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, gammadelta T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vgamma5+ gammadelta T cells, which were replaced by gammadelta T-cell subsets (mainly Vgamma6+ gammadeltalowCCR2+CCR6-) actively producing IL-17A. Consistent with a proangiogenic role, gammadelta T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ gammadelta T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated gammadelta T-cell subpopulations, thereby promoting angiogenesis and cancer development. [less ▲]

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See detailSystematic functional perturbations uncover a prognostic genetic network driving human breast cancer
Gallenne, Tristan; Ross, Kenneth N.; Visser, Nils L. et al

in Oncotarget (2017), 8(13), 20572-20587

Prognostic classifiers conceivably comprise biomarker genes that functionally contribute to the oncogenic and metastatic properties of cancer, but this has not been investigated systematically. The ... [more ▼]

Prognostic classifiers conceivably comprise biomarker genes that functionally contribute to the oncogenic and metastatic properties of cancer, but this has not been investigated systematically. The transcription factor Fra-1 not only has an essential role in breast cancer, but also drives the expression of a highly prognostic gene set. Here, we systematically perturbed the function of 31 individual Fra-1-dependent poor-prognosis genes and examined their impact on breast cancer growth in vivo. We find that stable shRNA depletion of each of nine individual signature genes strongly inhibits breast cancer growth and aggressiveness. Several factors within this ninegene set regulate each other’s expression, suggesting that together they form a network. The ninegene set is regulated by estrogen, ERBB2 and EGF signaling, all established breast cancer factors. We also uncover three transcription factors, MYC, E2F1 and TP53, which act alongside Fra-1 at the core of this network. ChIP-Seq analysis reveals that a substantial number of genes are bound, and regulated, by all four transcription factors. The nine-gene set retains significant prognostic power and includes several potential therapeutic targets, including the bifunctional enzyme PAICS, which catalyzes purine biosynthesis. Depletion of PAICS largely cancelled breast cancer expansion, exemplifying a prognostic gene with breast cancer activity. Our data uncover a core genetic and prognostic network driving human breast cancer. We propose that pharmacological inhibition of components within this network, such as PAICS, may be used in conjunction with the Fra-1 prognostic classifier towards personalized management of poor prognosis breast cancer. [less ▲]

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See detailELP3 links tRNA modification to IRES-dependent translation of LEF-1 to promote metastasis in breast cancer
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Tharun, Lars et al

in Journal of Experimental Medicine (2016), 213

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the ... [more ▼]

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis. [less ▲]

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See detailThe Innate Immune Response of Equine Bronchial Epithelial Cells is Altered by Training
Frellstedt, Linda ULiege; Gosset, Philippe; Kervoaze, Gwenola et al

in Veterinary Research (2015), 46(3), 1-12

Respiratory diseases, including inflammatory airway disease (IAD), viral and bacterial infections, are common problems in exercising horses. The airway epithelium constitutes a major physical barrier ... [more ▼]

Respiratory diseases, including inflammatory airway disease (IAD), viral and bacterial infections, are common problems in exercising horses. The airway epithelium constitutes a major physical barrier against airborne infections and plays an essential role in the lung innate immune response mainly through toll-like receptor (TLR) activation. The aim of this study was to develop a model for the culture of equine bronchial epithelial cells (EBEC) in vitro and to explore EBEC innate immune responses in trained horses. Bronchial epithelial biopsies were taken from 6 adult horses during lower airway endoscopy. EBEC were grown in vitro by an explant method. The innate immune response of EBEC was evaluated in vitro by treatment with TLR ligands. TLR3 is the most strongly expressed TLR at the mRNA level in EBEC and stimulation of EBEC with Poly(I:C), an analog of viral dsRNA, triggers a strong secretion of IFN-β, TNF-α, IL-6 and CXCL8. We further evaluated the EBEC innate immune response in horses that underwent a 4-month-training program. While training had no effect on TLR mRNA expression in EBEC as well as in bronchial biopsies, it increased the production of IFN-β after stimulation with a TLR3 ligand and decreased the secretion of TNF-α and IL-6 after stimulation with a TLR2 and TLR3 ligand. These findings may be implicated in the increased risk for viral and bacterial infections observed in sport horses. Altogether, we report a successful model for the culture of EBEC that can be applied to the investigation of pathophysiologic conditions in longitudinal studies. [less ▲]

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See detailGeneration and validation of a mouse model for conditional inactivation of PLAGL1
Pirottin, Dimitri ULiege; Schurmans, Stéphane ULiege; Francois, Cédric ULiege et al

in Proceedings of the 4th edition : FARAH Day 2014 (2014)

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See detailIncreased hypoxia-inducible factor 1alpha expression in lung cells of horses with recurrent airway obstruction.
Toussaint, Marie ULiege; Fievez, Laurence ULiege; Desmet, Christophe ULiege et al

in BMC Veterinary Research (2012), 8(1), 64

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological ... [more ▼]

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-alpha in myeloid cells in horse with recurrent airway obstruction. RESULTS: In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-alpha mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-alpha mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. CONCLUSION: Taken together, our results suggest an important role for Hif1-alpha in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO. [less ▲]

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