Figure 2

Chronic inflammation leads to fibrosis in skeletal-muscle repair. Resident and extravasating peripheral macrophages play an important role in the early stages of muscle repair after acute injury, with pro-inflammatory (M1) macrophages first acting to clear the damage, and anti-inflammatory (M2c) macrophages and alternatively activated macrophages (M2a), implicated in the subsequent resumption of inflammation, extracellular matrix (ECM) deposition and tissue repair. M2c and M2a macrophages release anti-inflammatory cytokines and pro-fibrotic molecules such as transforming growth factor (TGF)-β, which in turn activate fibroblasts in a regulated manner to produce ECM components and ECM-remodeling factors, including autocrine production of TGFβ, collagen, fibronectin, serine proteases (such as uPA/plasmin), and metalloproteinases (MMPs) and their inhibitors (TIMPs). However, during chronic tissue damage, as in muscular dystrophies, the increased and persistent presence of macrophages modify the intensity, duration and interactions of these released factors, leading to excessive ECM accumulation and replacement of muscle with fibrotic tissue.