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Influence de la protéine découplante mitochondriale UCP2 sur la signalisation et le métabolisme des macrophages

Abstract : Uncoupling Protein UCP2 belogns to the familly of carrier proteins of the inner mitochondrial membrane. UCP2 protein expression is restricted to some tissues such as spleen, stomac or intestine. At cellular level, UCP2 is mostly present in macrophages where it controls the production of reactive oxygen species (ROS). Analysis of Ucp2-KO mice showed their better resistance to an infection by Toxoplasma gondii than wil-type animals thanks to higly active macrophages in terms of ROS production. In a murine model of human atherosclerosis, Ucp2-KO mice developed increased atherosclerotic lesions. Plaques in Ucp2-KO animals contained much more macrophages et nitric oxide (NO)-induced damage.
My thesis work was mainly focused on the mechanisms involved in the modulation of immune responses by UCP2.
We demonstrated that the quick downregulation of UCP2 in response to LPS potentiates MAPK activation in macrophages. Mictochondria through UCP2 is in the heart of a signal amplification loop involving mitochondrial ROS. As a consequence, signaling and activation of Ucp2-KO macrophages is accelerated, leading to increased production of NO and cytokines.
The relevance of these data was next investigated in vivo in the framework of infection and autoimmunity. Mice infection with Listeria monocytogenes revealed a better resistance of Ucp2-KO mice. Higher production of pro-inflammatory cytokines in Ucp2-KO mice and increased recrutement of phagocytes in spleen highlight the regulatory function of UCP2 on innate immunity. Regarding autoimmunity, the developement of experimental type 1 diabetes is strongly accelerated in Ucp2-KO mice. Ucp2-KO macrophages played a the crucial rôle in pathogenesis due to their higher capacity to produce NO and cytokines.
The biochemcal activity of UCP2, ie its transport activity, was also studied. Glutamine specifically induced the expression of UCP2. As a consequence, comparison of glutamine metabolism in Ucp2-KO and Ucp2-WT macrophages revealed that UCP2 is required to accurate oxidation of glutamine.
Finally, the availability of whole genomes of several species allowed the realization of a phylogenomic study in order to understand the evolution of UCPs.
My work showed for the first time a role for UCP2 as a key component of a signal amplification loop involving mitochondria. More importantly it highlighted UCP2 as a new player in the framework of type 1 diabetes. Future research on the development of strategies to induce UCP2 or to inhibit its downregulation in immune cells may be promising in the context of autoimmunity.
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Submitted on : Friday, October 26, 2007 - 4:02:00 PM
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Yalin Emre. Influence de la protéine découplante mitochondriale UCP2 sur la signalisation et le métabolisme des macrophages. Biologie cellulaire. Université René Descartes - Paris V, 2007. Français. ⟨tel-00182672⟩

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