AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration.
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;AMPKα1(fl/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.
INSERM, Institut Cochin, Paris, France.
Rémi
R
Mounier
Marine
M
Théret
Ludovic
L
Arnold
Sylvain
S
Cuvellier
Laurent
L
Bultot
Olga
O
Göransson
Nieves
N
Sanz
Arnaud
A
Ferry
Kei
K
Sakamoto
Marc
M
Foretz
Benoit
B
Viollet
Bénédicte
B
Chazaud
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D012038:Regeneration / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
C548179:Prkaa1 protein, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases