Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis [INNATE IMMUNITY AND INFLAMMATION]

Key Points

  • IRCTX muscle injury results in muscle fibrosis through macrophage-derived TGF-β1.

  • FAPs respond to TGF-β1 by differentiating into fibroblasts.

  • Conditional knockout and systemic inhibition of TGF-β1 attenuates IRCTX fibrosis.

Visual Abstract

Figure1

Abstract

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell–derived TGF-β1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of Tgfb1 abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-β1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.

Footnotes

  • D.M.S. was supported by a Plastic Surgery Foundation National Endowment Award, C.H. was supported by a Howard Hughes Medical Institute Medical Research Fellowship, and M.S. was supported by a Plastic Surgery Foundation National Endowment Award. B.L. was supported by National Institutes of Health (NIH)/National Institute of General Medical Sciences Grant K08GM109105, NIH Grant R01GM123069, an American College of Surgeons Clowes Award, U.S. Department of Defense Grants W81XWH-18-1-0653 (OR170174) and W81XWH-17-1-0655 (OR160105), and the International Fibrodysplasia Ossificans Progressiva Association. M.T.L. was funded by California Institute for Regenerative Medicine Clinical Fellow Training Grant TG2-01159, an American Society of Maxillofacial Surgeons/Maxillofacial Surgeons Foundation Research Grant Award, the Hagey Laboratory for Pediatric Regenerative Medicine, the Oak Foundation, NIH Grant U01 HL099776, and the Gunn/Olivier Fund. The Department of Radiology, the Center for Molecular Imaging, and the Preclinical Imaging and Computational Analysis Shared Resource at the University of Michigan are supported in part by Comprehensive Cancer Center NIH Grant P30 CA046592. Research reported in this article was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under Award P30 AR069620. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

  • The sequencing data presented in this article have been submitted to the Gene Expression Omnibus database under accession number GSE144270.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    CTX
    cardiotoxin
    ECM
    extracellular matrix
    eMHC
    embryonic myosin H chain
    FAP
    fibroadipogenic progenitor
    GEM
    gel bead-in-emulsion
    GO
    gene ontology
    IF
    immunofluorescence
    IR
    ischemia reperfusion
    PCA
    principal component analysis
    POD
    postoperative day
    TA
    tibialis anterior
    t-SNE
    t-distributed stochastic neighbor embedding
    UMI
    unique molecular identifier
    WT
    wild-type.
  • Received August 5, 2019.
  • Accepted January 20, 2020.

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