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Mononuclear phagocytes in cardiometabolic diseases

Principal investigator :
Philippe Lesnik, Ph.D.

This team is focused on the study of mononuclear phagocytes in the context of cardiometabolic diseases. The team main objective is to better understand how different mononuclear phagocytes subsets impact on chronic metabolic disorders, with particular emphasis on macrophages and dendritic cells. To this aim, unique mouse models and preclinical approaches are used to decipher the complex interactions between mononuclear phagocytes subsets and metabolic tissues. In addition, this team builds on recent cutting-edge preclinical and clinical proof-of-concepts evidencing a relationship between intestinal microbiota, immune cells and cholesterol metabolism in the host.

This team is attached to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

Principal investigator groups:

Emmanuel Gautier‘s group works on the diversity and functionality of mononuclear cell subsets in cardiometabolic diseases. His group is interested in delineating the role of mononuclear phagocytes (monocytes, macrophages and dendritic cells) in chronic inflammatory conditions such as cardiometabolic diseases (atherosclerosis, obesity, NASH). More specifically, we study how dendritic cell subsets, tissue resident and monocyte-derived macrophages impact on cardiometabolic diseases development, and developed tools to target these subsets in vivo. Our studies are based on integrated approaches combining molecular, cellular biology and animal models. Particular attention is given to the interactions between inflammatory stimuli, mononuclear phagocytes, lipid and carbohydrate metabolisms as well as the gut microbiota.

Dr. Thierry Huby’s main research focuses on understanding the role of tissue resident and monocyte-derived macrophages in cholesterol metabolism given particular attention to specific cellular players, such as the scavenger receptor SCARB1, but also, specific tissue macrophage populations such as Kupffer cells. Our experimental approaches mainly involve use of mouse models to target candidate genes and cell types to evaluate their contribution in vivo in maintaining cholesterol homeostasis in the context of cardio-metabolic diseases.

FOCUS

This team is focused on the study of mononuclear phagocytes in the context of cardiometabolic diseases. The team main objective is to better understand how different mononuclear phagocytes subsets impact on chronic metabolic disorders, with particular emphasis on macrophages and dendritic cells.


BIOSKETCH

Philippe Lesnik obtained his Ph.D. in Molecular and Cellular Biology at the University of Pierre and Marie Curie in 1993. From 1999-2002 he was a Visiting Investigator at the Gladstone Institute of Cardiovascular Disease, University of California. He was head of the INSERM U939 “Dyslipidemias, Inflammation and Atherosclerosis in Metabolic Diseases” which merged with 5 other teams in 2014 forming a large research entity (INSERM U1166) working on CardioMetabolic Diseases. He currently leads the research team “Mononuclear phagocytes in cardiometabolic diseases”. Dr. Lesnik has a strong background in lipoprotein metabolism and atherosclerosis, as well as developing mouse models to dissect in vivo the physiopathological mechanisms that contribute to the progression or regression of the disease. Dr. Lesnik places particular emphasis on the role of cellular players of the innate and adaptive immunity, cellular regulatory networks influenced by environmental and metabolic changes and key cellular lipid sensors/receptors. He developed transgenic mouse strains enriched or depleted in mononuclear cells to explore the relationships between the immune system and atherosclerosis. He has discovered a strong inverse relationship between dendritic cell populations and plasma cholesterol levels. The hypothesis is that dendritic cells actively participate in the control of gut microbiota composition, therefore selecting specific bacterial communities, which can differentially affect steroid transformation (cholesterol, faecal sterols and primary and secondary biliary acids). Such bacterial species may consequently influence dietary cholesterol availability and the absorption of sterols from the enterohepatic cycle and thus have effects on cholesterol excretion. In this context, Dr. Lesnik addresses cholesterol metabolism by the gut microbiota and its consequences on cholesterolemia and atherosclerosis development.


Publications

Elevated CETP activity improves plasma cholesterol efflux capacity from human macrophages in women. Villard EF, El Khoury P, Duchene E, Bonnefont-Rousselot D, Clement K, Bruckert E, Bittar R, Le Goff W, Guerin M. Arterioscler Thromb Vasc Biol. 2012 Oct;32(10):2341-9.

Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Camont L, Lhomme M, Rached F, Le Goff W, Nègre-Salvayre A, Salvayre R, Calzada C, Lagarde M, Chapman MJ, Kontush A. Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2715-23.

Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Gautier EL, Ivanov S, Lesnik P, Randolph GJ. Blood. 2013 Oct 10;122(15):2714-22.

Adrenocortical scavenger receptor class B type I deficiency exacerbates endotoxic shock and precipitates sepsis-induced mortality in mice. Gilibert S, Galle-Treger L, Moreau M, Saint-Charles F, Costa S, Ballaire R, Couvert P, Carrié A, Lesnik P, Huby T. J Immunol. 2014 Jul 15;193(2):817-26.

Adipocyte ATP-binding cassette G1 promotes triglyceride storage, fat mass growth, and human obesity. Frisdal E, Le Lay S, Hooton H, Poupel L, Olivier M, Alili R, Plengpanich W, Villard EF, Gilibert S, Lhomme M, Superville A, Miftah-Alkhair L, Chapman MJ, Dallinga-Thie GM, Venteclef N, Poitou C, Tordjman J, Lesnik P, Kontush A, Huby T, Dugail I, Clement K, Guerin M, Le Goff W. Diabetes. 2015 Mar;64(3):840-55.

Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE. Bouchareychas L, Pirault J, Saint-Charles F, Deswaerte V, Le Roy T, Jessup W, Giral P, Le Goff W, Huby T, Gautier EL, Lesnik P. Cardiovascular Res. 2015 in press.