Autocrine IL-6 drives cell and extracellular matrix anisotropy in scar fibroblasts

Fiona Kenny, Stefania Marcotti, Deandra Belo De Freitas, Elena Drudi, Vivienne Leech, Rachel Bell, Jennifer Easton, María-del-Carmen Díaz-de-la-Loza, Roland Fleck, Leanne Allison, Christina Philippeos, Angelika Manhart, Tanya Shaw*, Brian Stramer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue. ECM anisotropy develops after rapid initiation of a fibroblast supracellular actin network, suggesting that cell alignment initiates ECM patterning. Keloid fibroblasts produce elevated levels of IL-6, and autocrine IL-6 production is both necessary and sufficient to induce cell and ECM alignment, as evidenced by ligand stimulation of normal dermal fibroblasts and treatment of keloid fibroblasts with the function blocking IL-6 receptor monoclonal antibody, tocilizumab. Downstream of IL-6, supracellular organization of keloid fibroblasts is controlled by activation of cell-cell adhesion. Adhesion formation inhibits contact-induced cellular overlap leading to nematic organization of cells and an alignment of focal adhesions. Keloid fibroblasts placed on isotropic ECM align the pre-existing matrix, suggesting that focal adhesion alignment leads to active anisotropic remodeling. These results show that IL-6-induced fibroblast cooperativity can control the development of a nematic ECM, highlighting both IL-6 signaling and cell-cell adhesions as potential therapeutic targets to inhibit this common feature of fibrosis.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalMatrix Biology
Volume123
Early online date13 Sept 2023
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Keloid
  • Fibrosis
  • Fibroblast
  • Scar
  • Extracellular Matrix
  • IL-6 (interleukin 6)

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