Research ArticleFibrosis

Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration

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Science Signaling  11 Aug 2020:
Vol. 13, Issue 644, eaau2803
DOI: 10.1126/scisignal.aau2803

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Inflammation cross-links fibronectin

The extracellular matrix (ECM) component fibronectin contributes to wound healing and tissue repair as both a structural element and a signaling molecule. Locy et al. found that fibrillar, but not soluble, fibronectin underwent oxidative cross-linking under inflammatory conditions that activated human lung fibroblasts. This reaction required fibroblast-produced H2O2 and a peroxidase, such as myeloperoxidase, which is produced by inflammatory cells. Dityrosine–cross-linked fibronectin was resistant to proteolytic degradation, inhibited the migration of human lung epithelial cells and fibroblasts, and was increased in both a mouse model of lung fibrosis and interstitial lung disease patients. How this modification affects cell migration is unknown, but it likely plays a role in both normal tissue repair and fibrosis.


The oxidation of tyrosine residues to generate o,o′-dityrosine cross-links in extracellular proteins is necessary for the proper function of the extracellular matrix (ECM) in various contexts in invertebrates. Tyrosine oxidation is also required for the biosynthesis of thyroid hormone in vertebrates, and there is evidence for oxidative cross-linking reactions occurring in extracellular proteins secreted by myofibroblasts. The ECM protein fibronectin circulates in the blood as a globular protein that dimerizes through disulfide bridges generated by cysteine oxidation. We found that cellular (fibrillar) fibronectin on the surface of transforming growth factor–β1 (TGF-β1)–activated human myofibroblasts underwent multimerization by o,o′-dityrosine cross-linking under reducing conditions that disrupt disulfide bridges, but soluble fibronectin did not. This reaction on tyrosine residues required both the TGF-β1–dependent production of hydrogen peroxide and the presence of myeloperoxidase (MPO) derived from inflammatory cells, which are active participants in wound healing and fibrogenic processes. Oxidative cross-linking of matrix fibronectin attenuated both epithelial and fibroblast migration and conferred resistance to proteolysis by multiple proteases. The abundance of circulating o,o′-dityrosine–modified fibronectin was increased in a murine model of lung fibrosis and in human subjects with interstitial lung disease compared to that in control healthy subjects. These studies indicate that tyrosine can undergo stable, covalent linkages in fibrillar fibronectin under inflammatory conditions and that this modification affects the migratory behavior of cells on such modified matrices, suggesting that this modification may play a role in both physiologic and pathophysiologic tissue repair.

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