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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

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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 1

Nonredundant role of ANXA1 in cardiotoxin-induced muscle injury and repair.

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Nonredundant role of ANXA1 in cardiotoxin-induced muscle injury and repa...
(A) Experimental setup. Acute injury was induced by cardiotoxin (CTX) injection in the tibialis anterior (TA) of WT, AnxA1–/–, and Fpr2/3–/– mice. Muscles were analyzed 0, 7, and 28 days after injury. (B) TA mass normalized to mouse body weight. (C) H&E staining of muscles 28 days after injury. Scale bar: 50 μm. Myofiber cross-sectional area (D), number of nuclei per myofiber (E), and lipid accumulation (F) in muscles 28 days after CTX injury. (G and H) Macrophage subtype analysis 2 days after CTX injury. Shown are the percentage of pro- and antiinflammatory macrophages within the F4/80+ population (G) and the resolution index (H). Results are mean ± SEM of at least 3 animals. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT.

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