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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization
Laura Formentini1, Fulvio Santacatterina1, Cristina Núñez de Arenas1
1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Abstract:
Mitochondria are signaling hubs in cellular physiology that play a role in inflammatory diseases. We found that partial inhibition of the mitochondrial ATP synthase in the intestine of transgenic mice triggers an anti-inflammatory response through NFκB activation mediated by mitochondrial mtROS. This shielding phenotype is revealed when mice are challenged by DSS-induced colitis, which, in control animals, triggers inflammation, recruitment of M1 pro-inflammatory macrophages, and the activation of the pro-oncogenic STAT3 and Akt/mTOR pathways. In contrast, transgenic mice can polarize macrophages to the M2 anti-inflammatory phenotype. Using the mitochondria-targeted antioxidant MitoQ to quench mtROS in vivo, we observe decreased NFκB activation, preventing its cellular protective effects. These findings stress the relevance of mitochondrial signaling to the innate immune system and emphasize the potential role of the ATP synthase as a therapeutic target in inflammatory and other related diseases.
Insights
Partial inhibition of mitochondrial ATP synthase in mice triggers an anti-inflammatory response via mitochondrial reactive oxygen species (mtROS) and NFκB activation, offering a potential therapeutic target for inflammatory diseases.
Area of Science:
- Cellular Physiology
- Immunology
- Mitochondrial Biology
Background:
- Mitochondria act as crucial signaling hubs in cellular physiology.
- Mitochondrial dysfunction is implicated in the pathogenesis of inflammatory diseases.
Purpose of the Study:
- To investigate the role of mitochondrial ATP synthase inhibition in modulating inflammatory responses.
- To explore the underlying mechanisms involving mitochondrial reactive oxygen species (mtROS) and NFκB signaling.
Main Methods:
- Utilized transgenic mice with partial inhibition of mitochondrial ATP synthase.
- Induced colitis using DSS (dextran sodium sulfate) to model inflammatory bowel disease.
- Administered MitoQ, a mitochondria-targeted antioxidant, to assess the role of mtROS.
Main Results:
- Partial ATP synthase inhibition induced an anti-inflammatory phenotype in mice challenged with DSS-induced colitis.
- This phenotype was mediated by NFκB activation through mtROS, promoting M2 macrophage polarization.
- Inhibition of mtROS with MitoQ abolished the protective effects, highlighting the critical role of mtROS.
Conclusions:
- Mitochondrial signaling is integral to the innate immune system.
- Partial inhibition of mitochondrial ATP synthase confers protection against experimental colitis.
- Mitochondrial ATP synthase represents a potential therapeutic target for inflammatory diseases.
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