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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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.
The authors declare no competing financial interests.
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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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