Journal
JOURNAL OF PATHOLOGY
Volume 253, Issue 4, Pages 366-373Publisher
WILEY
DOI: 10.1002/path.5618
Keywords
integrin; fibrosis; α SMA; TGFβ nephronectin; integrin α 8β 1; monoclonal antibody; drug; translation
Funding
- Japanese Society for Promotion of Research KAKENHI [24659367, 26293174, 17H04161]
- Agency for Medical Research and Development (AMED) Japan, Translational Research Program A111, via Kyushu University
- Grants-in-Aid for Scientific Research [26293174, 24659367, 17H04161] Funding Source: KAKEN
Ask authors/readers for more resources
The study identified integrin alpha 8 subunit as the most upregulated in fibroblasts during liver fibrosis, showing relevance to HSC activation, fibroblast differentiation, and TGF beta activation. Experimentally, anti-alpha 8 neutralizing mAb improved pathology and fibrosis markers in murine fibrosis models. The findings suggest integrin alpha 8 beta 1 as a potential target for anti-fibrotic drugs in treating liver fibrosis.
No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin alpha-subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture-activated HSCs and specifically expressed across fibroblast linages was the alpha 8 subunit. An anti-alpha 8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non-alcoholic steatohepatitis-associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and alpha-smooth muscle actin) were improved following the mAb injection. We also CCl4-treated mice with inducible Itga8-/-; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC alpha 8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast alpha 8 activated latent TGF beta. Finally, integrin alpha 8 beta 1 potentially fulfils the growing need for anti-fibrotic drugs and is an integrin not to be ignored. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available