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 5

Null or reduced AMPK expression affects ANXA1-mediated macrophage polarization.

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Null or reduced AMPK expression affects ANXA1-mediated macrophage polari...
(A and B) Primary macrophages derived from WT or AMPKα1–/– mice were treated with 10 nM hrANXA1, and the percentage of cells expressing the proinflammatory markers iNOS and CCL3 (A) and the antiinflammatory markers TGF-β1, CD163, and CD206 (B) was determined by immunofluorescence. (C–E) Human PBMC–derived macrophages were transfected by a nontargeting or 3 different AMPKα1-targeting siRNAs and treated with 10 nM hrANXA1 for 24 hours. AMPKα1 protein level was determined by FACS (C), and the MFI units of the proinflammatory MHCII (D) and antiinflammatory CD206 (E) markers were measured by flow cytometry. (F–I) Conditioned medium produced by murine macrophages was transferred onto murine primary myoblasts, and their fusion was measured by immunofluorescence. (F) Experimental setup. (G) Representative images of desmin (red) and Hoechst (blue) labeling of myoblast cultures. Scale bar: 50 μm. (H and I) Fusion index calculated after desmin labeling. Shown are the means ± SEM of the independent experiments relative to the WT control (H) and the raw results of each individual replicate (I). Results are mean ± SEM of at least 3 independent experiments. *P < 0.05, **P < 0.01 vs. mock or control; ##P < 0.01 vs. WT.