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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/111072
Role of Mfn2 in Macrophage Inflammatory Responses
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[eng] Mitochondria are well known for their role as bioenergetic and biosynthetic organelles. Recently, they also have emerged as one of the main regulators of innate immune responses, mostly for its ability to modulate several signaling pathways through mechanisms such ROS production. Mitofusin-2 (Mfn2) is a GTPase located in the external mitochondrial and ER membranes. It is responsible for the fusion between mitochondria and the ER-mitochondria contacts, both necessary for the correct functioning of both organelles. Even that, the role of Mfn2 in immune responses. Here we demonstrate that Mfn2 is crucial for the pro-inflammatory activation of macrophages. Murine Mfn2-/- macrophages show a disruption in the mitochondrial network morphology that leads to loss in the mitochondrial membrane potential and in mitochondrial respiration. These two defects in the mitochondrial function do not affect their ability to normally generate ATP. However, the production of ROS in the mitochondria from Mfn2-/- macrophages is markedly decreased. This defect in ROS generation leads to a severe dysfunction in macrophage responses, particularly in the inflammatory activation, phagocytosis, and the processing of proteins. First, the decrease in ROS in Mfn2-/- macrophages results in a defective activation of p38, ERK, and NF-kB signaling pathways in response to LPS. The decrease in these signaling cascades leads to a reduction in the production of pro- inflammatory cytokines, severely impairing their ability to undergo pro- inflammatory activation. Second, in addition to show reduced ROS levels, Mfn2-/- also show an accumulation of autophagosomes due to a Mfn2-dependent defect in the autophagosome-lysosome fusion. As a result to both increased autophagy and decreased ROS levels, Mfn2-/- macrophages show decreased expression of type- A scavenger receptors. We demonstrate that these alterations lead to a widespread defect in the phagocytic capabilities of Mfn2-/- macrophages, showing defective phagocytosis of bacteria (both gram positive and gram negative) and apoptotic bodies. Thirdly, Mfn2-/- macrophages also show a defect in the bactericidal activity of phagocyted bacteria, as well as a defective proteolysis, being unable to process antigens to present them to CD4+ cells in a MHC-II context, and therefore, potentially impairing their ability to initiate adaptive immune responses. Finally, we demonstrated that Mfn2 is relevant in in vivo models of inflammation or infection. Myeloid-conditional Mfn2-/- mice were infected with either Listeria monocytogenes or Mycobacterium tuberculosis. In both models, Mfn2-/- mice showed a severe decrease in their survival, when compared to their WT counterparts. Furthermore, the colony counts in selected organs (spleen and liver for listeria, spleen and lung for tuberculosis) was significantly increased in Mfn2-/- mice, indicating that Mfn2 in macrophages is required to effectively control bacterial infections. In addition, we performed a model of sterile inflammation using the irritant DNFB on the mice’s ear. Confirming the in vitro results, Mfn2-/- mice show decreased inflammation in the ear, as confirmed by the decrease in size and weight, and the reduced expression of inflammatory cytokines. All these findings suggest that Mfn2 is a crucial regulator of macrophage pro- inflammatory responses, including production of pro-inflammatory cytokines, phagocytosis, and antigen presentation, through modulation of mitochondrial ROS production, autophagy, and protein processing.
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TUR TORRES, Juan. Role of Mfn2 in Macrophage Inflammatory Responses. [consulta: 15 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/111072]