Abstract
The communication between macrophages and tendon cells plays a critical role in regulating the tendon-healing process. However, the potential mechanisms through which macrophages can control peritendinous fibrosis are unknown. Our data showed a strong pro-inflammatory phenotype of macrophages after a mouse tendon–bone injury. Moreover, by using a small-molecule compound library, we identified an aldehyde dehydrogenase inhibitor, disulfiram (DSF), which can significantly promote the transition of macrophage from M1 to M2 phenotype and decrease macrophage pro-inflammatory phenotype. Mechanistically, DSF targets gasdermin D (GSDMD) to attenuate macrophage cell pyroptosis, interleukin-1β, and high mobility group box 1 protein release. These pro-inflammatory cytokines and damage-associated molecular patterns are essential for regulating tenocyte and fibroblast proliferation, migration, and fibrotic activity. Deficiency or inhibition of GSDMD significantly suppressed peritendinous fibrosis formation around the injured tendon and was accompanied by increased regenerated bone and fibrocartilage compared with the wild-type littermates. Collectively, these findings reveal a novel pathway of GSDMD-dependent macrophage cell pyroptosis in remodeling fibrogenesis in tendon–bone injury. Thus, GSDMD may represent a potential therapeutic target in tendon–bone healing.
Highlights
Peritendinous fibrosis is a critical complication arising after tendon injury (TI), which is primarily identified as excessive extracellular matrix (ECM) deposition and fibroblast cell activation (Manske, 2005; Juneja et al, 2013)
We investigated the potential role of macrophage and ECM proteins in TI
We have revealed a critical role of DSF in macrophage polarization and peritendinous fibrosis
Summary
Peritendinous fibrosis is a critical complication arising after tendon injury (TI), which is primarily identified as excessive extracellular matrix (ECM) deposition and fibroblast cell activation (Manske, 2005; Juneja et al, 2013). While the resident tissue fibroblasts have been identified as sensitive to intrinsic mechanical and biophysical cues in tendon–bone injury (Zheng et al, 2017; Yao et al, 2019), the initiation of immune response in this process remains poorly understood. M1 macrophages can produce different pro-inflammatory cytokines such as interleukin-1β (IL1β) and tumor necrosis factor-α (TNF-α) during immune activation. These pro-inflammatory cytokines have an increased level in the early process of TI and modulate tendon–bone response after magnetic stimulation. The precise mechanisms that can regulate M2 macrophage polarization and function in the tendon–bone injury are unknown
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