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

J Clin Invest. 2020 Mar 2;130(3):1156-1167. doi: 10.1172/JCI124635.


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.

Keywords: Homeostasis; Inflammation; Macrophages; Muscle Biology; Protein kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Annexin A1 / genetics
  • Annexin A1 / metabolism*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal* / injuries
  • Muscle, Skeletal* / physiology
  • Receptors, Formyl Peptide / genetics
  • Receptors, Formyl Peptide / metabolism
  • Regeneration*
  • Signal Transduction*


  • Adaptor Proteins, Signal Transducing
  • Annexin A1
  • HSH2 protein, mouse
  • Receptors, Formyl Peptide
  • annexin A1, mouse
  • formyl peptide receptor 2, mouse
  • AMP-Activated Protein Kinases