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 2

Infiltrating myeloid cell–derived ANXA1 controls muscle repair.

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Infiltrating myeloid cell–derived ANXA1 controls muscle repair. (A) West...
(A) Western blot analysis of ANXA1 protein in total TA muscle. Muscles were analyzed 0, 1, 2, 4, 7, and 14 days after injury. Shown are representative blots (top) and quantification of ANXA1 to β-actin (bottom) and ratios. (B) Quantitative reverse transcriptase PCR analysis of AnxA1 mRNA level in various cell populations FACS-sorted from TA muscle. Muscles were analyzed 0, 1, 2, 4, 7, and 14 days after injury. EC, endothelial cells; FAP, fibro/adipogenic progenitors; SAT, satellite cells; Mac, macrophages; Neut, neutrophils. (C) Experimental setup of bone marrow transplantation (BMT). CX3CR1-GFP mice were irradiated and then transplanted with bone marrow cells isolated from WT or AnxA1–/– mice. Bone marrow engraftment was checked on a blood sample after around 5 weeks. Then animals were injured in their TA by CTX injection and muscles analyzed 0 or 28 days later. Engraftment was confirmed on the bone marrow of each animal on the day of sacrifice. H&E staining (D) and myofiber cross-sectional area (E) of TA muscles 28 days after CTX injury. Scale bar: 50 μm. Results are mean ± SEM of at least 2 (D14 in A) or 3 muscles. *P < 0.05, **P < 0.01 vs. WT or D0.