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<p>Systemic sclerosis is an autoimmune connective tissue disease of unknown cause and diverse clinical manifestations. Vasospastic episodes (Raynaud’s phenomenon), often triggered by cold or stress, typically appear at disease onset. Cytokines, particularly TGF-β, act in the inflammatory and hypoxic microenvironment to drive fibrosis, which predominantly develops at inflammatory sites. Several cell types contribute to disease pathogenesis and fibrosis, including vascular endothelial cells, vascular smooth muscle cells, and fibroblasts in the extracellular matrix. Multiple signaling pathways are activated in these cells and promote disease progression. Endothelial and vascular smooth muscle cells respond to diverse ligands through pathways such as AKT, MAPK, and GPCR signaling, which promote fibrosis progression in the profibrotic and proinflammatory milieu. Cytokines are also important mediators of inflammation and fibrosis, particularly by acting on activated monocytes in the ECM and guiding them toward M1 or M2 macrophage polarization. In the early inflammatory stage, M1 macrophages predominate, while the fibrotic stage is characterized by increased M2 macrophage presence. ECM accumulation, resulting from TGF-β signaling in fibroblasts, provides integrins with ligands and promotes enhanced adhesion and migration of these cells. TGF-β, on the other hand, can transactivate the Ras pathway, promoting myofibroblast differentiation and enhancing pro-fibrotic effects.</p>

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Systemic sclerosis, main culprits and involved signaling pathways

  • 期刊论文

  • 发表日期：

    2025年11月6日

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  • Omid Sadatpour,
  • Amin Azizan,
  • Hoda kavosi,
  • Mohammad Vodjgani,
  • Elham Farhadi,
  • Mahdi Mahmoudi

摘要

Systemic sclerosis is an autoimmune connective tissue disease of unknown cause and diverse clinical manifestations. Vasospastic episodes (Raynaud’s phenomenon), often triggered by cold or stress, typically appear at disease onset. Cytokines, particularly TGF-β, act in the inflammatory and hypoxic microenvironment to drive fibrosis, which predominantly develops at inflammatory sites. Several cell types contribute to disease pathogenesis and fibrosis, including vascular endothelial cells, vascular smooth muscle cells, and fibroblasts in the extracellular matrix. Multiple signaling pathways are activated in these cells and promote disease progression. Endothelial and vascular smooth muscle cells respond to diverse ligands through pathways such as AKT, MAPK, and GPCR signaling, which promote fibrosis progression in the profibrotic and proinflammatory milieu. Cytokines are also important mediators of inflammation and fibrosis, particularly by acting on activated monocytes in the ECM and guiding them toward M1 or M2 macrophage polarization. In the early inflammatory stage, M1 macrophages predominate, while the fibrotic stage is characterized by increased M2 macrophage presence. ECM accumulation, resulting from TGF-β signaling in fibroblasts, provides integrins with ligands and promotes enhanced adhesion and migration of these cells. TGF-β, on the other hand, can transactivate the Ras pathway, promoting myofibroblast differentiation and enhancing pro-fibrotic effects.