Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation
Simon McArthur, … , Mauro Perretti, Rémi Mounier
Simon McArthur, … , Mauro Perretti, Rémi Mounier
Published February 4, 2020
Citation Information: J Clin Invest. 2020;130(3):1156-1167. https://doi.org/10.1172/JCI124635.
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Research Article Inflammation Muscle biology

Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation

Abstract

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration.

Authors

Simon McArthur, Gaëtan Juban, Thomas Gobbetti, Thibaut Desgeorges, Marine Theret, Julien Gondin, Juliana E. Toller-Kawahisa, Chris P. Reutelingsperger, Bénédicte Chazaud, Mauro Perretti, Rémi Mounier

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Figure 4

The ANXA1–FPR2/ALX pathway activates the AMPK signaling cascade in human and murine macrophages.

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The ANXA1–FPR2/ALX pathway activates the AMPK signaling cascade in human...
(A) Schematic representation of the ANXA1–FPR2/ALX signaling cascade. (B–D) Western blot analysis of phosphorylated CaMK, AMPKα1, and acetyl-CoA carboxylase (ACC) in human PBMC–derived macrophages treated with hrANXA1. Shown are representative blots (B) and quantification of p-AMPKα1/AMPKα1 (C) and p-ACC/ACC (D) ratios. (E) Representative Western blot (top) and quantification (bottom) of p-AMPKα/AMPKα1 ratio in human PBMC–derived macrophages treated by hrANXA1 in the presence or absence of 10 μM WRW4. (F) Representative Western blot (left) and quantification (right) of p-AMPKα/AMPKα1 ratio in WT or Fpr2/3–/– murine bone marrow–derived macrophages treated with hrANXA1. Results are mean ± SEM of at least 2 (D) or 3 (C, E, and F) independent experiments. *P < 0.05, **P < 0.01 vs. vehicle.