Jonathan Vanhoutte

University of Lille Nord de France, Lille, Nord-Pas-de-Calais, France

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Publications (13)60.62 Total impact

  • Annales de Dermatologie et de Vénéréologie 06/2014; 141(6-7 Suppl 2):S84. · 0.60 Impact Factor
  • Annales de Dermatologie et de Vénéréologie 01/2014; 141(s 6–7):S84. · 0.60 Impact Factor
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    ABSTRACT: Introduction Des analyses d’association de gènes montrent que le locus CDKN2A/B qui code notamment la protéine p16INK4a, pourrait être associé au développement des maladies coronariennes, de l’athérosclérose et du diabète de type 2. Ces pathologies sont associées à l’expansion et à l’inflammation de différents dépôts de tissu adipeux (TA), notamment le tissu adipeux périvasculaire (PVAT). p16INK4a est un régulateur du cycle cellulaire cependant sa fonction dans l’adipogenèse reste encore inconnue. Matériels et méthodes Dans cette étude, nous avons étudié le rôle de p16INK4a dans l’adipogenèse in vitro en utilisant des préadipocytes 3T3L1 transfectés par un siRNA-CDKN2A ou des fibroblastes embryonnaires (MEF) isolés des souris p16+/+ et p16−/−, et in vivo, chez l’homme, en étudiant l’expression de p16INK4a dans le PVAT, et chez la souris, en étudiant le développement des dépôts de TA induit par un traitement Rosiglitazone. Le rôle de p16INK4a dans le développement du PVAT à partir de la moelle osseuse a été étudié chez des souris chimères p16−/−LDLRKO et p16+/+LDLRKO soumises à un régime western. Résultats La diminution de l’expression de p16INK4a dans les pré-adipocytes 3T3L1 augmente l’adipogenèse, mesurée par une augmentation de l’expression de PPARgamma, adiponectine, perilipine et CEBPalpha et une accumulation de lipides, sans affecter l’expansion clonale. Des résultats similaires ont été obtenus dans les MEF p16−/−. Chez l’homme, p16INK4a est fortement exprimé dans le PVAT cardiaque comparé aux autres dépôts de TA. Chez la souris, bien que la déficience de p16INK4a n’influence pas le développement des différents dépôts de TA, le traitement des souris p16−/− par la Rosiglitazone augmente spécifiquement le développement du PVAT, associé à une augmentation de l’expression de marqueurs de cellules précurseurs des adipocytes de la moelle. La déficience de p16INK4a dans la moelle osseuse de souris chimères p16−/− LDLRKO augmente le développement du PVAT induit par un régime western. Conclusion L’ensemble de ces données démontre un nouveau rôle de p16INK4a dans l’adipogenèse et le développement du PVAT.
    Diabetes & Metabolism. 01/2014; 40:A2.
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    ABSTRACT: Rationale: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective: The objective of this study is, first, to better characterize the iron distribution and metabolism in macrophage sub-populations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the Liver X Receptors (LXR). Methods and Results: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and Mannose Receptor (MR) positive (CD68+MR+) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favouring iron accumulation. However, upon iron exposure, M2 macrophages acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extra-cellular LDL by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68+MR+ macrophages accumulate oxidized lipids, which activate Liver X Receptors (LXRα and LXRβ resulting in the induction of ABCA1, ABCG1 and ApoE expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 (NRF2) expression, hence increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions: These data identify a role for M2 macrophages in iron handling, a process which is regulated by LXR activation.
    Circulation Research 09/2013; · 11.86 Impact Factor
  • International journal of cardiology 07/2013; · 6.18 Impact Factor
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    ABSTRACT: OBJECTIVE: Abdominal aortic aneurysms (AAAs), dilations of the infrarenal aorta, are characterized by inflammation and oxidative stress. We previously showed increased levels of peroxiredoxin-1 (PRDX-1) in macrophages cultured from AAA patients. The purpose of the study was to determine which subpopulation of macrophages is present in AAAs and is involved in upregulation of PRDX-1 in aneurysmal disease. METHODS AND RESULTS: This study used immunohistochemistry with antibodies against CD68 and mannose receptor (MR) to determine the subtype of macrophages in AAA tissue samples (n=33); laser capture microdissection to isolate each subtype; and quantitative-reverse transcriptase-polymerase chain reaction, Western blot, and ELISA to assess PRDX-1 mRNA and PRDX-1protein levels in both types. Proinflammatory CD68(+)MR(-) macrophages predominated in adventitial tissue, whereas the intraluminal thrombus contained CD68(+)MR(+) macrophages. The presence of lipids and iron-containing deposits confirmed their phagocytic phenotype. Laser capture microdissection-isolated CD68(+)MR(-) and CD68(+)MR(+) macrophages, characterized by quantitative-reverse transcriptase-polymerase chain reaction (TNF, IL1B, MRC1, and CCL18) and Western blot (stabilin and hemoglobin), validated the microdissected subtypes. PRDX-1 expression was colocalized with CD68(+)MR(-) macrophages. PRDX-1 mRNA and PRDX-1 protein were both more abundant in CD68(+)MR(-) than CD68(+)MR(+) macrophages in AAA. CONCLUSIONS: These findings suggest that the proteins or mRNAs expressed by the proinflammatory CD68(+)MR(-) macrophages may contribute to aneurysmal pathology.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2012; · 6.34 Impact Factor
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    ABSTRACT: A genomic region near the CDKN2A locus, encoding p16(INK4a), has been associated to type 2 diabetes and atherosclerotic vascular disease, conditions in which inflammation plays an important role. Recently, we found that deficiency of p16(INK4a) results in decreased inflammatory signaling in murine macrophages and that p16(INK4a) influences the phenotype of human adipose tissue macrophages. Therefore, we investigated the influence of immune cell p16(INK4a) on glucose tolerance and atherosclerosis in mice. Bone marrow p16(INK4a)-deficiency in C57Bl6 mice did not influence high fat diet-induced obesity nor plasma glucose and lipid levels. Glucose tolerance tests showed no alterations in high fat diet-induced glucose intolerance. While bone marrow p16(INK4a)-deficiency did not affect the gene expression profile of adipose tissue, hepatic expression of the alternative markers Chi3l3, Mgl2 and IL10 was increased and the induction of pro-inflammatory Nos2 was restrained on the high fat diet. Bone marrow p16(INK4a)-deficiency in low density lipoprotein receptor-deficient mice did not affect western diet-induced atherosclerotic plaque size or morphology. In line, plasma lipid levels remained unaffected and p16(INK4a)-deficient macrophages displayed equal cholesterol uptake and efflux compared to wild type macrophages. Bone marrow p16(INK4a)-deficiency does not affect plasma lipids, obesity, glucose tolerance or atherosclerosis in mice.
    PLoS ONE 01/2012; 7(3):e32440. · 3.53 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPARα-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/- apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/-, and PPARα-/- apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
    Arteriosclerosis Thrombosis and Vascular Biology 07/2011; 31(7):1573-9. · 6.34 Impact Factor
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    ABSTRACT: The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMϕ) or alternatively (AAMϕ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16(INK4a) deficiency (p16(-/-)) modulates the macrophage phenotype. Transcriptome analysis revealed that p16(-/-) BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4-induced macrophage polarization. In line with this observation, p16(-/-) BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16(-/-) BM displayed higher hepatic AAMϕ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMϕ phenotype skewing. Surprisingly, p16(-/-) BMDMs did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.
    Blood 06/2011; 118(9):2556-66. · 9.78 Impact Factor
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    ABSTRACT: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown. Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.
    Circulation Research 02/2011; 108(8):985-95. · 11.86 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2011; 12(1):95-95.
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2011; 12(1):95-95.
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    ABSTRACT: Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice. T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls. The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans.
    PLoS ONE 01/2010; 5(1):e8722. · 3.53 Impact Factor