The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis

Nat Commun. 2015 Oct 15:6:8574. doi: 10.1038/ncomms9574.

Abstract

Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Animals, Newborn
  • Chemokines / metabolism
  • Extracellular Matrix / metabolism
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Fibroblasts / physiology
  • Fibrosis / etiology*
  • Fibrosis / metabolism
  • Humans
  • Inflammation / complications
  • Male
  • Mice, Transgenic
  • Middle Aged
  • Phenotype
  • Recombinant Proteins / metabolism*
  • Skin / pathology*
  • Snail Family Transcription Factors
  • Transcription Factors / genetics

Substances

  • Chemokines
  • Extracellular Matrix Proteins
  • Fbln5 protein, mouse
  • Recombinant Proteins
  • Snail Family Transcription Factors
  • Transcription Factors