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Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors

Nature Medicine volume 21, pages 786–794 (2015)Cite this article

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Abstract

Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β−rich environment favors fibrotic degeneration of the muscle during chronic injury.

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Figure 1: After their damage-induced expansion, excess FAPs undergo apoptosis.
Figure 2: FAP clearance is impaired during skeletal muscle regeneration in Ccr2−/− mice.
Figure 3: Macrophages induce FAP death via TNF signaling.
Figure 4: TNF blockade leads to increased FAP survival and collagen deposition.
Figure 5: Tgf-β1 expression during muscle regeneration.
Figure 6: Inhibition of Tgf-β1 signaling by nilotinib restores FAP apoptosis in mdx mice.

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Acknowledgements

We thank the Biomedical Research Centre Animal Facility and core staff as well as the University of British Columbia flow cytometry facility staff for their technical assistance. We are very grateful to Claudia Hopkins for schematic presented in Supplementary Figure 10. The Col1a1*3.6-eGFP mice were a gift from D.W. Rowe (Center for Regenerative Medicine and Skeletal Development, University of Connecticut Health Center). This work was supported by a grant from the Heart and Stroke Foundation of Canada, the Canadian Institute for Health Research grant MOP 97856 (both to F.M.V.R.), and a Russian Science Foundation grant #14-50-00029 (to S.A.N.). F.B. was supported by a Four-Year Doctoral Fellowship (4YF) by the University of British Columbia, and M.L. was supported by a fellowship from the Chilean government.

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Authors and Affiliations

  1. Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    Dario R Lemos, Farshad Babaeijandaghi, Marcela Low, Chih-Kai Chang, Sunny T Lee, Regan-Heng Zhang, Anuradha Natarajan & Fabio M V Rossi

  2. Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Dario R Lemos, Farshad Babaeijandaghi, Marcela Low, Chih-Kai Chang, Regan-Heng Zhang, Anuradha Natarajan & Fabio M V Rossi

  3. Department of Experimental Medicine, Section of Medical Pathophysiology Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy

    Daniela Fiore

  4. Engelhardt Institute of Molecular Biology, Moscow, Russia

    Sergei A Nedospasov

  5. Lomonosov Moscow State University, Moscow, Russia

    Sergei A Nedospasov

  6. German Rheumatism Research Center, Berlin, Germany

    Sergei A Nedospasov

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  1. Dario R Lemos
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Contributions

D.R.L. designed, directed and carried out experiments; analyzed data; and wrote the manuscript. F.B., M.L., C.-K.C., S.T.L., D.F., R.-H.Z. and A.N. carried out experiments and analyzed data. S.A.N. provided important advice on experimental design. F.M.V.R. designed experiments, directed the project and wrote the manuscript.

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Correspondence to Fabio M V Rossi.

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Lemos, D., Babaeijandaghi, F., Low, M. et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med 21, 786–794 (2015). https://doi.org/10.1038/nm.3869

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