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IMmunity and MEtabolism in DIAbetes:
IMMEDIAT Lab

Our team, “Immunity and Metabolism in Diabetes”, investigates the multi-faceted regulation of inflammatory processes and immunity in diabetes and its complications and comorbidities. At the center of our scientific interest is the innate immune response in diabetes. Indeed macrophages (tissue innate immune cells) and their circulating monocyte progenitors are responsible for sensing, integrating and responding to a myriad of stimuli from their micro-environment. Abnormal activation of macrophages or monocytes is a key pathogenic component of diabetes and its numerous complications linked to inflammation, i.e. liver disease, cardiovascular disease, nephropathy, retinopathy etc. A better understanding of the role that immune responses, namely metabolic inflammation, play in diabetes (pathogenesis and complications) is crucial for the development of novel personalized, preventative and therapeutic approaches.

Our fundamental research strategy operates in 4 themes:

- Epigenomic Control of Metabolic Inflammation in Diabetes (Theme 1)
- Metabolic Regulation of Inflammation (Theme 2)
- Immuno-Regulation of Pancreatic Islets (Theme 3)
- System’s Biology and Data Integration (Them 4)

An extremely important aspect of the IMMEDIAB team is the high translational capacity of projects. This is owed to the fact that half of the team’s senior scientists are also clinicians. The tight link with medical practice ensures clinical relevance of the fundamental research carried out at the bench representing IMMEDIAB’s Transversal axis: Human clinical cohorts.

To reach our aims, we are developing large-scale approaches using innovative bioinformatics and complex system modelling tools. Ensuring translatability, our investigations are carried out in well-phenotyped diabetic subjects with a range of vascular complications and at various disease stages and from whom clinical datasets and biobanks are being constructed. This strategy generates hypotheses of putative novel cellular and molecular pathophysiological actors, which are then tested in vitro and through extensive ex vivo modelling. Therapeutic potential of defined molecular actors is investigated through pre-clinical models (transgenic and knockout models, feeding, environmental and surgical challenges). Very active recruitment of new patient cohorts, lead by clinical team members, allows the efficient return from bench-to-bedside, testing back hypotheses driven by the in vitro and in vivo models.

Figure legend: 1. Oil red O staining of intracellular lipids (red) and DAPI nuclear staining (blue) in alternatively activated bone marrow-derived macrophages against phase-contrast. 2. Immunoflourescence staining of adipose tissue section with adipocyte membrane marker Perilipin (green) and murine macrophage marker F4/80 (red). 3. Immunohistochemistry staining of MAC-2 macrophages (brown) in a mouse pancreatic islet undergoing metabolic stress. 4. Chromatin-immunoprecipitation peak-maps coupled to RNA sequencing heatmap from tissue macrophages.

 

 

 

Theme 1: Epigenomic Control of Metabolic Inflammation in Diabetes
PI: Nicolas Venteclef (DR Inserm)

Gene-environment interactions are gaining recognition for their functional consequences driven through epigenetic mechanisms. Such mechanisms are increasingly recognized for their control over innate immune differentiation and function. The mechanisms that govern monocyte and macrophage plasticity, and thereby achieve specialized functional roles, are incompletely understood. In recent years, it has become clear that on the genome scale, DNA sequences called enhancers, more so than promoters, orchestrate the majority of cell-type-specific patterns of gene expression, particularly in monocytes and macrophages. Our hypothesis is that alteration of enhancer activities promotes aberrant monocyte and macrophage activation and uncontrolled inflammatory response, which underlie the susceptibility to develop T2D and its complications. Uncontrolled inflammatory responses may accelerate the diabetogenesis process and favor diabetic complications.

Theme 2: Metabolic Regulation of Inflammation
PI: Fawaz Alzaid (CRCN Inserm)

Immune effector cells complement their production of cytokine-chemokine mediators by compartmentalising cellular bioenergetics to cytoplasmic glycolysis of mitochondrial respiration. This phenomenon remains to be studied in the diabetic state, the particularity of which is systemic dysmetabolism and an abundance of substrates. We investigate the therapeutic potential of interfering with the cellular ‘bioenergetic toggle’ in inflammatory metabolic diseases. We apply a combination of metabolic and immunologic analyses at the cellular and systemic levels, extensively applying in vitro, ex vivo and mechanistic preclinical models.

Theme 3: Immuno-Regulation of Pancreatic Islets
PI: Elise Dalmas (CRCN Inserm – ATIP Avenir)

Increasing evidence suggests a role for the immune system to finely tune the endocrine function of pancreatic islets. Within islets, beta cells have to dynamically respond to fluctuating insulin demands of the body, from daily needs after food intake to complex physiological processes. We propose the concept that local immunity is part of the endocrine system and that resident immune cells contribute to beta cell adaptive responses to metabolic stress. Therefore, our project aims at exploring the cellular interactions between beta cells, innate immune cells (macrophages, group 2 innate lymphoid cells…) and endothelial cells occurring in islets when facing metabolic adjustments.

Theme 4: Systems’ Biology and Data Integration
PIs: Frederic. Fumeron (MCU) and Gilberto. Velho (CRCN INSERM)

Multilevel data integration is a central objective that supports full exploitation of results from our research towards the identification of novel pathways, predictors and biomarkers associated with the development of diabetes complications. This theme has both applicative and methodological objectives while being transversal to other research themes. One objective is to pursue in-depth multi-omic data analysis (epigenomic, genomic, transcriptomic and metabolomic) of the heterogeneous data produced and used in the laboratory, which involves developing original tools when needed. This approach also involves integrative systems biology outlook where we will unravel individual susceptibility to diabetes and its complications based on bio-clinical and multi-omic data integration with epigenetic and genetic data analyses. One of the deliverables will be a set of new integrative-quantitative markers of chronic exposure to hyperglycemia. 


Transversal Axis: Human clinical cohorts
PIs: Jean-Francois Gautier and Ronan Roussel (PU-PHs, Lariboisière and Bichat Claude Bernard Paris Hospitals)

A key aspect of our project is that the fundamental findings (observed in vivo and in vitro) will be validated in cohorts of well-phenotyped subjects including uncomplicated diabetics, diabetics with complications at different stages and healthy control subjects. Our team will be particularly involved in phenotyping patients for 1) systemic low-grade inflammation including circulating monocyte phenotypes, 2) defining the epigenetic index involved with diabetes complications. The PIs (R. Roussel and J.F. Gautier) have constituted several major cohorts investigating pathogenesis of T2D and its complications: DESIR (5000 French participants from the community, with a 9 year follow-up of clinical data and repeated plasma/serum/urine sampling); EPITHERAPY (150 patients with higher risk to developing T2D, with clinical data and biological sampling), DIABHYCAR (5000 participants developing T2D, with clinical data and biological sampling, 5 year follow-up for renal and cardiovascular outcomes); ANGIOSAFE (5200 T2D patients with different vascular complications (retinopathy and cardiovascular outcomes, with clinical data and biological sampling, 3 year follow-up for retinopathy and cardiovascular outcomes).

 

Team Leader:  Nicolas VENTECLEF (DR; Inserm)

Deputy Leader:  Jean-François GAUTIER (PU-PH; Paris Diderot)

 

Team Members:

Researchers: Fawaz ALZAID (CR; Inserm), Konstantinos ARAPIS (PH; AP-HP),  Elise DALMAS (CR; Inserm), Frédéric FUMERON (MCU; Univ Paris Diderot), Michel MARRE (PU-PH; Univ Paris Diderot),  Louis POTIER (MCU-PH; Univ Paris Diderot), Jean-Pierre RIVELINE (PU-PH; Univ Paris Diderot), Ronan ROUSSEL (PU-PH; Univ Paris Diderot), Laura SABLONE (Chef Projet; CDD), Antoine SOPRANI (PH, Générale de santé), Laurence TRAVERT (MCU-PH; Univ Paris Diderot), Claire VANDIEDONCK (MCU-PH; Univ Paris Diderot), Gilberto VELHO (CR; Inserm).

Technical Staff: Raphaelle BALLAIRE (IE; CDD), Bertrand BAUCHAT (Adj Tec; Univ Paris Descartes), Catherine CHOLLET (Tech, Inserm), Tina ELJALMANESH (AI; CDD), Maryse GENDRY (Adj Tec; Inserm), Andreia GONCALVES (AI; CDD).

Young Researchers:  Elena CARCARINO (Post-Doc), Joyce CUENCO (Post-Doc), Karima DRARENI (PhD Student), Sylvain GIRARDO (PhD Student), Jean-Baptiste JULLA (PhD Student), Abdul MOUTAIROU (PhD Student), Lucie ORLIAGUET (PhD Student), Manuel SANCHEZ (PhD Student).

Publications

  • Dalmas E. Innate immune priming of insulin secretion. Curr Opin Immunol. 2018  Oct 17;56:44-49. 
  •  Drareni K, Ballaire R, Barilla S, Mathew MJ, Toubal A, Fan R, Liang N, Chollet C, Huang Z, Kondili M, Foufelle F, Soprani A, Roussel R, Gautier JF, Alzaid F, Treuter E, Venteclef N. GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation. Cell Rep. 2018 Sep11;24(11):2957-2971.e6.
  • El Boustany R, Tasevska I, Meijer E, Kieneker LM, Enhörning S, Lefèvre G, Mohammedi K, Marre M, Fumeron F, Balkau B, Bouby N, Bankir L, Bakker SJ, Roussel  R, Melander O, Gansevoort RT, Velho G. Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population. JCI Insight. 2018 Jul 12;3(13). pii: 121479.
  • Bumbu A, Moutairou A, Matar O, Fumeron F, Velho G, Riveline JP, Gautier JF, Marre M, Roussel R, Potier L. Non-severe hypoglycaemia is associated with weight  gain in patients with type 1 diabetes: Results from the Diabetes Control and Complication Trial. Diabetes Obes Metab. 2018 May;20(5):1289-1292.
  • Gauci ML, Boudou P, Baroudjian B, Vidal-Trecan T, Da Meda L, Madelaine-Chambrin I, Basset-Seguin N, Bagot M, Pages C, Mourah S, Resche-Rigon M, Pinel S, Sassier M, Rouby F, Eftekhari P, Lebbé C, Gautier JF. Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study. Cancer Immunol Immunother. 2018 Aug;67(8):1197-1208.
  • Dalmas E, Lehmann FM, Dror E, Wueest S, Thienel C, Borsigova M, Stawiski M, Traunecker E, Lucchini FC, Dapito DH, Kallert SM, Guigas B, Pattou F, Kerr-Conte  , Maechler P, Girard JP, Konrad D, Wolfrum C, Böni-Schnetzler M, Finke D, Donath MY. Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin secretion through Myeloid Cell Retinoic Acid Production. Immunity. 2017 Nov 21;47(5):928-942.e7.
  • Dos Santos RS, Daures M, Philippi A, Romero S, Marselli L, Marchetti P, Senée V, Bacq D, Besse C, Baz B, Marroquí L, Ivanoff S, Masliah-Planchon J, Nicolino M, Soulier J, Socié G, Eizirik DL, Gautier JF, Julier C. dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure. Diabetes. 2017 Apr;66(4):1086-1096.
  • Dror E, Dalmas E, Meier DT, Wueest S, Thévenet J, Thienel C, Timper K, Nordmann TM, Traub S, Schulze F, Item F, Vallois D, Pattou F, Kerr-Conte J, Lavallard V, Berney T, Thorens B, Konrad D, Böni-Schnetzler M, Donath MY. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol. 2017 Mar;18(3):283-292.
  • Alzaid F, Lagadec F, Albuquerque M, Ballaire R, Orliaguet L, Hainault I, Blugeon C, Lemoine S, Lehuen A, Saliba DG, Udalova IA, Paradis V, Foufelle F, Venteclef N. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight. 2016 Dec 8;1(20):e88689.
  • Fan R, Toubal A, Goñi S, Drareni K, Huang Z, Alzaid F, Ballaire R, Ancel P, Liang N, Damdimopoulos A, Hainault I, Soprani A, Aron-Wisnewsky J, Foufelle F, Lawrence T, Gautier JF, Venteclef N, Treuter E. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nat Med. 2016 Jul;22(7):780-91.
  • Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG, Ancel P, Lacombe A, Ling Y, Allatif O, Cruciani-Guglielmacci C, André S, Viguerie N, Poitou C, Stich V, Torcivia A, Foufelle F, Luquet S, Aron-Wisnewsky J, Langin D, Clément K, Udalova IA, Venteclef N. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med. 2015 Jun;21(6):610-8.
  • Velho G, El Boustany R, Lefèvre G, Mohammedi K, Fumeron F, Potier L, Bankir L, Bouby N, Hadjadj S, Marre M, Roussel R. Plasma Copeptin, Kidney Outcomes, Ischemic Heart Disease, and All-Cause Mortality in People With Long-standing Type 1 Diabetes. Diabetes Care. 2016 Dec;39(12):2288-2295.
  • Steg PG, Roussel R. Randomized Trials to Evaluate Cardiovascular Safety of Antihyperglycemic Medications: A Worthwhile Effort? Circulation. 2016 Aug 23;134(8):571-3.

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