Respiratory Research (Apr 2021)

Tropomyosin 2.1 collaborates with fibronectin to promote TGF-β1-induced contraction of human lung fibroblasts

  • Peta Bradbury,
  • Cassandra P. Nader,
  • Aylin Cidem,
  • Sandra Rutting,
  • Dianne Sylvester,
  • Patrick He,
  • Maria C. Rezcallah,
  • Geraldine M. O’Neill,
  • Alaina J. Ammit

DOI
https://doi.org/10.1186/s12931-021-01730-y
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 10

Abstract

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Abstract Many lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.

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