Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction

Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C(C156S)therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4(+)and CD8(+)T cells potently suppress, in part through interferon-gamma, cardiac lymphangiogenesis post-MI. Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C-C156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.Peer reviewe

Epigenetic control of myeloid cells-induced cardiac angiogenesis and lymphangiogenesis

La régulation épigénétique de la méthylation de la lysine 27 de l'histone H3 (H3K27) a été récemment mise en évidence comme une étape clé de la polarisation en macrophages alternatifs de type M2, essentiels pour la réparation cardiaque après un infarctus du myocarde (IDM).Nous avons émis l'hypothèse que l’enzyme épigénétique EZH2, responsable de la méthylation de H3K27, pourrait agir comme un point de contrôle épigénétique au cours de ce processus. Nous démontrons pour la première fois une localisation cytoplasmique ectopique et potentiellement inactive de l'enzyme épigénétique EZH2, lors de la différenciation des monocytes en macrophages M2 in vitro ainsi que dans les macrophages M2 in vivo au cours d'une inflammation cardiaque post-IDM. De plus, nous montrons que l'inhibition pharmacologique d'EZH2, avec le GSK-343, résout la méthylation de H3K27 au niveau du promoteur des gènes bivalents, améliorant ainsi leur expression pour promouvoir les fonctions de réparation des monocytes humains. Conformément à cet effet protecteur, le traitement avec le GSK-343 accélère la résolution inflammatoire cardiaque empêchant l'expansion de la zone lésée et le dysfonctionnement cardiaque post-IDM in vivo.En conclusion, notre étude révèle que la modulation épigénétique des cellules immunitaires infiltrant le coeur peut être prometteuse pour limiter le remodelage cardiaque indésirable post-IDM.Epigenetic regulation of histone H3 lysine 27 (H3K27) methylation has recently emerged as a key step during alternative M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI).We hypothesized that the epigenetic enzyme EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first-time that EZH2 ectopically localizes to the cytoplasm, where it may be inactive, during monocytes differentiation into M2 macrophages in vitro as well as in M2 polarized macrophages in vivo during cardiac inflammation post-MI. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation at the promoter of bivalent genes, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction post-MI in vivo.In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling post-MI

Contrôle épigénétique de l'angiogenèse et de la lymphangiogenèse cardiaque induit par les cellules myéloïdes.

Epigenetic regulation of histone H3 lysine 27 (H3K27) methylation has recently emerged as a key step during alternative M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI).We hypothesized that the epigenetic enzyme EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first-time that EZH2 ectopically localizes to the cytoplasm, where it may be inactive, during monocytes differentiation into M2 macrophages in vitro as well as in M2 polarized macrophages in vivo during cardiac inflammation post-MI. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation at the promoter of bivalent genes, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction post-MI in vivo.In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling post-MI.La régulation épigénétique de la méthylation de la lysine 27 de l'histone H3 (H3K27) a été récemment mise en évidence comme une étape clé de la polarisation en macrophages alternatifs de type M2, essentiels pour la réparation cardiaque après un infarctus du myocarde (IDM).Nous avons émis l'hypothèse que l’enzyme épigénétique EZH2, responsable de la méthylation de H3K27, pourrait agir comme un point de contrôle épigénétique au cours de ce processus. Nous démontrons pour la première fois une localisation cytoplasmique ectopique et potentiellement inactive de l'enzyme épigénétique EZH2, lors de la différenciation des monocytes en macrophages M2 in vitro ainsi que dans les macrophages M2 in vivo au cours d'une inflammation cardiaque post-IDM. De plus, nous montrons que l'inhibition pharmacologique d'EZH2, avec le GSK-343, résout la méthylation de H3K27 au niveau du promoteur des gènes bivalents, améliorant ainsi leur expression pour promouvoir les fonctions de réparation des monocytes humains. Conformément à cet effet protecteur, le traitement avec le GSK-343 accélère la résolution inflammatoire cardiaque empêchant l'expansion de la zone lésée et le dysfonctionnement cardiaque post-IDM in vivo.En conclusion, notre étude révèle que la modulation épigénétique des cellules immunitaires infiltrant le coeur peut être prometteuse pour limiter le remodelage cardiaque indésirable post-IDM

Contrôle épigénétique de l'angiogenèse et de la lymphangiogenèse cardiaque induit par les cellules myéloïdes.

Epigenetic regulation of histone H3 lysine 27 (H3K27) methylation has recently emerged as a key step during alternative M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI).We hypothesized that the epigenetic enzyme EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first-time that EZH2 ectopically localizes to the cytoplasm, where it may be inactive, during monocytes differentiation into M2 macrophages in vitro as well as in M2 polarized macrophages in vivo during cardiac inflammation post-MI. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation at the promoter of bivalent genes, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction post-MI in vivo.In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling post-MI.La régulation épigénétique de la méthylation de la lysine 27 de l'histone H3 (H3K27) a été récemment mise en évidence comme une étape clé de la polarisation en macrophages alternatifs de type M2, essentiels pour la réparation cardiaque après un infarctus du myocarde (IDM).Nous avons émis l'hypothèse que l’enzyme épigénétique EZH2, responsable de la méthylation de H3K27, pourrait agir comme un point de contrôle épigénétique au cours de ce processus. Nous démontrons pour la première fois une localisation cytoplasmique ectopique et potentiellement inactive de l'enzyme épigénétique EZH2, lors de la différenciation des monocytes en macrophages M2 in vitro ainsi que dans les macrophages M2 in vivo au cours d'une inflammation cardiaque post-IDM. De plus, nous montrons que l'inhibition pharmacologique d'EZH2, avec le GSK-343, résout la méthylation de H3K27 au niveau du promoteur des gènes bivalents, améliorant ainsi leur expression pour promouvoir les fonctions de réparation des monocytes humains. Conformément à cet effet protecteur, le traitement avec le GSK-343 accélère la résolution inflammatoire cardiaque empêchant l'expansion de la zone lésée et le dysfonctionnement cardiaque post-IDM in vivo.En conclusion, notre étude révèle que la modulation épigénétique des cellules immunitaires infiltrant le coeur peut être prometteuse pour limiter le remodelage cardiaque indésirable post-IDM

Inter-organizational learning within innovation projects : critical stages, issues and good practices

In September 2005, the Walloon Government decided to adopt “the Walloon Marshall Plan”, one of the priorities of which is the setting up of competitiveness clusters bringing together different contributors (businesses, private & public research centres and training centres). In this context, our aim is to understand how the businesses and the research and training centres are managing to put in place partnership dynamics in order to create innovative projects. To achieve this, we have chosen to focus primarily on the dynamics of inter-organizational learning. Consequently, within the five competitiveness clusters set up in mid-2006, we have opted to focus in particular on 4 projects which have emerged from them. The conceptual model upon which we have based our initiative is structured around this aim and makes use of various analytical benchmarks. Inspired in particular by the work of Holmqvist (2003), this model constitutes our reading and analysis framework for the projects selected from the four competitiveness clusters selected

Role of protective stoma after primary anastomosis for generalized peritonitis due to perforated diverticulitis—DIVERTI 2 (a prospective multicenter randomized trial): rationale and design (nct04604730)

International audienceAbstract Background Traditionally, patients with peritonitis Hinchey III and IV due to perforated diverticulitis were treated with Hartmann’s procedure. In the past decade, resection and primary anastomosis have gained popularity over Hartmann’s procedure and recent guidelines recommend Hartmann’s procedure in two situations only: critically ill patients and in selected patients with multiple comorbidity (at high risk of complications). The protective stoma (PS) is recommended after resection with primary anastomosis, however its interest has never been studied. The aim of this trial is to define the role of systematic PS after resection and primary anastomosis for peritonitis Hinchey III and IV due to perforated diverticulitis. Methods/design This DIVERTI 2 trial is a multicenter, randomized, controlled, superiority trial comparing resection and primary anastomosis with (control group) or without (experimental group) PS in patients with peritonitis Hinchey III and IV due to perforated diverticulitis. Primary endpoint is the overall 1 year morbidity according to the Clavien–Dindo classification of surgical complications. All complications occurring during hospitalization will be collected. Late complications occurring after hospitalization will be collected during follow-up. In order to obtain 80% power for a difference given by respective main probabilities of 67% and 47% in the protective stoma and no protective stoma groups respectively, with a two-sided type I error of 5%, 96 patients will have to be included in each group, hence 192 patients overall. Expecting a 5% rate of patients not assessable for the primary end point (lost to follow-up), 204 patients will be enrolled. Secondary endpoints are postoperative mortality, unplanned reinterventions, incisional surgical site infection (SSI), organ/space SSI, wound disruption, anastomotic leak, operating time, length of hospital stay, stoma at 1 year after initial surgery, quality of life, costs and quality-adjusted life years (QALYs). Discussion The DIVERTI 2 trial is a prospective, multicenter, randomized, study to define the best strategy between PS and no PS in resection and primary anastomosis for patients presenting with peritonitis due to perforated diverticulitis. Trial registration ClinicalTrial.gov: NCT04604730 date of registration October 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04604730?recrs=a&cond=Diverticulitis&draw=2&rank=12

Plasma Peptide Concentrations and Peptide-Reactive Immunoglobulins in Patients with Eating Disorders at Inclusion in the French EDILS Cohort (Eating Disorders Inventory and Longitudinal Survey)

International audienc

Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice—a new potential probiotic for appetite and body weight management

International audienc

Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI

Abstract Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation of bivalent gene promoters, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction in female mice post-MI in vivo. In conclusion, our study reveals that pharmacological epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

International audienceThe emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure−activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo