Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis
David M. Stepien, Charles Hwang, Simone Marini, Chase A. Pagani, Michael Sorkin, Noelle D. Visser, Amanda K. Huber, Nicole Edwards, Shawn Loder, Kaetlin Vasquez, Carlos A. Aguilar, Ravi Kumar, Shamik Mascharak, Michael T. Longaker, Jun Z. Li, Benjamin Levi
Abstract
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.