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AMPKα1 Regulates Macrophage Skewing at the Time of Resolution of Inflammation during Skeletal Muscle Regeneration

2013; Cell Press; Volume: 18; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2013.06.017

1932-7420

Rémi Mounier, Marine Théret, Ludovic Arnold, Sylvain Cuvellier, Laurent Bultot, Olga Göransson, Nieves Sanz, Arnaud Ferry, Kei Sakamoto, Marc Foretz, Benoı̂t Viollet, Bénédicte Chazaud,

Histone Deacetylase Inhibitors Research

Macrophages control the resolution of inflammation through the transition from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype. Here, we present evidence for a role of AMPKα1, a master regulator of energy homeostasis, in macrophage skewing that occurs during skeletal muscle regeneration. Muscle regeneration was impaired in AMPKα1−/− mice. In vivo loss-of-function (LysM-Cre;AMPKα1fl/fl mouse) and rescue (bone marrow transplantation) experiments showed that macrophagic AMPKα1 was required for muscle regeneration. Cell-based experiments revealed that AMPKα1−/− macrophages did not fully acquire the phenotype or the functions of M2 cells. In vivo, AMPKα1−/− leukocytes did not acquire the expression of M2 markers during muscle regeneration. Skewing from M1 toward M2 phenotype upon phagocytosis of necrotic and apoptotic cells was impaired in AMPKα1−/− macrophages and when AMPK activation was prevented by the inhibition of its upstream activator, CaMKKβ. In conclusion, AMPKα1 is crucial for phagocytosis-induced macrophage skewing from a pro- to anti-inflammatory phenotype at the time of resolution of inflammation.