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<p>Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis and tissue stiffness, in which monocytes and macrophages are increasingly recognized as key contributors to pro-fibrotic myofibroblast formation, although the underlying mechanisms remain incompletely understood. Here, we used a three-dimensional (3D) skin model to study how CD14<sup>+</sup> monocytes, M1 and M2-like macrophages induce fibroblasts activation and contraction in collagen type I hydrogels. We identified that the co-culture of dermal (myo)fibroblasts with monocytes displayed strong spontaneous hydrogel contraction, coupled with an upregulation of myofibroblast activation-associated markers, such as alpha-smooth muscle actin (α-SMA). Using transcription factor-responsive reporter constructs and small-molecule inhibitors, we demonstrated that monocytes-(myo)fibroblasts communication was mediated by JAK/STAT3 and TGF-β/Smad2/3 signaling pathways. Flow cytometry analyses revealed that monocytes, after interacting with (myo)fibroblasts, differentiated into a mixed M1/M2 polarization phenotype, characterized by CD163, CD206, CD86, and HLA-DR expression. Both M1 and M2-like macrophages promoted significant (myo)fibroblast contraction, which could be mimicked by supernatant transfer. TGF-β neutralization but not IL-6 blocking abolished this effect. This study demonstrates that monocytes/macrophages can strongly induce (myo)fibroblasts activation/contraction. Together, our work contributes to elucidating pathways and mechanisms associated with skin fibrosis in SSc and paves the way for developing new platforms for targeted therapy testing.</p>

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Monocytes strongly induce (myo)fibroblast contraction in a 3D skin model to understand inflammation-fibrosis crosstalk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月19日

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  • D. C. Zanin-Silva,
  • N. J. T. van Kooten,
  • T. I. Papadimitriou,
  • D. N. Dorst,
  • B. Walgreen,
  • E. L. Vitters,
  • M. H. J. van den Bosch,
  • M. I. Koenders,
  • A. P. M. van Caam

摘要

Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis and tissue stiffness, in which monocytes and macrophages are increasingly recognized as key contributors to pro-fibrotic myofibroblast formation, although the underlying mechanisms remain incompletely understood. Here, we used a three-dimensional (3D) skin model to study how CD14+ monocytes, M1 and M2-like macrophages induce fibroblasts activation and contraction in collagen type I hydrogels. We identified that the co-culture of dermal (myo)fibroblasts with monocytes displayed strong spontaneous hydrogel contraction, coupled with an upregulation of myofibroblast activation-associated markers, such as alpha-smooth muscle actin (α-SMA). Using transcription factor-responsive reporter constructs and small-molecule inhibitors, we demonstrated that monocytes-(myo)fibroblasts communication was mediated by JAK/STAT3 and TGF-β/Smad2/3 signaling pathways. Flow cytometry analyses revealed that monocytes, after interacting with (myo)fibroblasts, differentiated into a mixed M1/M2 polarization phenotype, characterized by CD163, CD206, CD86, and HLA-DR expression. Both M1 and M2-like macrophages promoted significant (myo)fibroblast contraction, which could be mimicked by supernatant transfer. TGF-β neutralization but not IL-6 blocking abolished this effect. This study demonstrates that monocytes/macrophages can strongly induce (myo)fibroblasts activation/contraction. Together, our work contributes to elucidating pathways and mechanisms associated with skin fibrosis in SSc and paves the way for developing new platforms for targeted therapy testing.