Transforming growth factor-β in tissue fibrosis

Abstract

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β-driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

Figure 1.

TGF-β secretion and activation in fibrotic tissues. Many different cell types, including macrophages, lymphocytes, epithelial cells, fibroblasts, pericytes (P), endothelial cells, and platelets (Plt), can produce and secrete TGF-β isoforms in sites of injury. The specific cellular origins of TGF-βs are dependent on the type of injury and on the cellular composition of the affected organ. TGF-βs are secreted in a latent form, typically as the tripartite LLC, comprised of mature TGF-β, its propeptide called LAP, and LTBP. Liberation of mature TGF-β from the latent form involves effects of proteases, integrin (ITG)-mediated actions, and contributions of specialized ECM proteins that may serve to localize the activation process or interact with LAP to release the active molecule. Active TGF-β binds to its receptors on the surface of the target cell, initiating signaling responses that promote fibrosis. SLC, small latent complex.

Figure 2.

The cellular targets of TGF-βs in tissue fibrosis. Although resident fibroblasts are major cellular targets of TGF-βs in fibrotic conditions, some TGF-β–mediated fibrogenic effects may involve actions on other cell types, including myeloid fibroblast progenitors (My), macrophages, epithelial cells, pericytes, and endothelial cells. TGF-β is a central mediator in fibroblast-to-myofibroblast conversion and promotes a matrix-preserving phenotype, associated with secretion of ECM proteins and tissue inhibitors of metalloproteinases (TIMPs). Some studies have suggested that expansion of myofibroblasts in fibrotic tissues may also involve TGF-β–mediated conversion of circulating progenitors, epithelial cells, pericytes, and endothelial cells into fibroblasts. TGF-β may also exert indirect activating effects on fibroblasts by promoting secretion of fibrogenic cytokines, growth factors, and matricellular proteins by macrophages, vascular cells, and epithelial cells.

Figure 3.

TGF-β signaling pathways in tissue fibrosis. TGF-β stimulates a matrix-preserving transcriptional program in fibroblasts by activating Smad-dependent and non-Smad pathways. TGF-βs bind to TβR complexes, comprising a single type II receptor (TβRII) and two forms of type I receptors (ALK5 or ALK1). ALK5 activates Smad2/3, whereas ALK1 activates Smad1/5/8. Although the role of the TβRII–ALK5–Smad2/3 axis in fibrosis is relatively well established, the potential significance of ALK1-Smad1/5/8 remains unclear. TGF-β–mediated activation of non-Smad cascades may also contribute to the fibrotic response. R-Smads exhibit an extensive network of interactions with non-Smad pathways. Fibrogenic TGF-β signaling is also modulated through accessory receptors, such as endoglin, betaglycan, and BAMBI. The complexity of TGF-β signaling pathways, the extensive cross-talk with other signaling networks, and the variable expression of coreceptors depending on the differentiation state of the cells and the microenvironment may explain the context-specific in vivo actions of TGF-βs.