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 3

Exogenous hrANXA1 controls human and mouse macrophage polarization in vitro.

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Exogenous hrANXA1 controls human and mouse macrophage polarization in vi...
Human PBMC–derived macrophages were incubated for 24 hours with lipopolysaccharide plus IFN-γ to promote an M1-like phenotype, before addition of human recombinant ANXA1 (hrANXA1; 10 nM) for a further 6 hours. (A and B) Median fluorescence intensity (MFI) units measured by flow cytometry of MHCII proinflammatory (A) and CD206 antiinflammatory (B) markers. Shown are MFI quantification (left) and representative FACS plots (right). (C–F) Quantitative reverse transcriptase PCR analysis of Tnfa (C) and Nos-2 (D) proinflammatory genes, and Il-10 (E) and Tgfb1 (F) antiinflammatory genes. (G and H) MFI units as measured by flow cytometry of MHCII proinflammatory (G) and CD206 antiinflammatory (H) markers after treatment by hrANXA1 in the presence or absence of the FPR2/ALX antagonist WRW4 (10 μM). Experiments were performed on PBMCs from 6 (A–F) or 3 (G and H) independent donors. Each color represents an independent PBMC donor. *P < 0.05 vs. vehicle; #P < 0.05 vs. control.