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Contrôle métabolique de la production et de la clairance des monocytes dans les pathologies inflammatoires

Abstract : Myeloid cells are produced by hematopoiesis, from hematopoietic stem cells (HSCs), a metabolically fine-tuned process. In chronic inflammatory diseases, an increased amount of monocytes is observed (monocytosis). My thesis focuses on the role of myeloid cells metabolism in chronic inflammatory diseases. We focused on the impact of cholesterol metabolism alterations into the anarchic proliferation of monocytes (carcinogenesis). Novel somatic mutations in the cholesterol efflux transporter ATP-Binding Cassette A1 induce carcinogenesis of monocytes, highlighting the impact of cholesterol efflux pathway in monocyte proliferation. I studied glycolysis in atherosclerosis, a chronic inflammatory disease. HSCs and myeloid progenitors exhibited higher Glut-1 expression in a murine model of atherosclerosis, with an enhanced accumulation of macrophages into lesions. A partial deletion of Glut-1 reduced HSCs and progenitors proliferation, limiting monocytosis and atherosclerotic plaques development. I studied the role of lysosomal acid lipase (LIPA) in the phagocytosis of apoptotic cells (efferocytosis). When a macrophage phagocytized an apoptotic cell, an important amount of cholesterol has to be degraded. LIPA is a key player in this process. When LIPA is inhibited, we observed a reduced production of 25- and 27-hydroxycholesterol, leading to an increased mitochondrial oxidative stress, which activated NLRP3 inflammasome activation and a reduced LXR activation. LIPA inhibition leads to a defective efferocytosis in vitro and in vivo. LIPA enzyme is essential to prevent metabolic inflammation by maintaining effective efferocytosis.
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https://tel.archives-ouvertes.fr/tel-01881169
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Submitted on : Tuesday, September 25, 2018 - 3:00:32 PM
Last modification on : Monday, October 12, 2020 - 10:28:19 AM
Long-term archiving on: : Wednesday, December 26, 2018 - 3:42:35 PM

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Manon Viaud. Contrôle métabolique de la production et de la clairance des monocytes dans les pathologies inflammatoires. Interactions cellulaires [q-bio.CB]. Université Côte d'Azur, 2018. Français. ⟨NNT : 2018AZUR4033⟩. ⟨tel-01881169⟩

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