Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization

Publication date: 9 May 2017
Source:Cell Reports, Volume 19, Issue 6
Author(s): Laura Formentini, Fulvio Santacatterina, Cristina Núñez de Arenas, Konstantinos Stamatakis, David López-Martínez, Angela Logan, Manuel Fresno, Ron Smits, Michael P. Murphy, José M. Cuezva
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.

Graphical abstract

Teaser

Formentini et al. demonstrate in vivo how the mitochondrial production of ROS in the intestinal epithelium leads to NFκB activation and the protection from inflammation through the recruitment of M2-macrophages, linking mitochondrial activity to the innate immune response of the tissue microenvironment.


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