Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis

Abstract

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 α‐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 α8 subunit. An anti‐α8 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 α‐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 α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFβ. Finally, integrin α8β1 potentially fulfils the growing need for anti‐fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Insights Into Transcriptome Profiles Associated With Wooden Breast Myopathy in Broilers Slaughtered at the Age of 6 or 7 Weeks

“…Corresponded with the current results, up-regulated ITGA8 was previously reported in broiler breast muscle affected by WS abnormality ( Marchesi et al, 2019 ), and in specimen of 90 patients with hepatic fibrosis ( Nishimichi et al, 2021 ). In addition, the same authors found that ITGA8 was minimally expressed in healthy liver, underlying its relevance with liver fibrosis.…”

Selective depletion of hepatic stellate cells‐specific LOXL1 alleviates liver fibrosis

“…Several lines of evidence support ITGA8 as a contributing factor to fibrosis development. [47][48][49][50] In liver disease, Liu et al indicated that ITGA8 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD) and in mice. Furthermore, they found that ITGA8 is involved in the pathogenesis of liver fibrosis in the course of NAFLD via the RhoA signaling pathway.…”

New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

“…Integrin α8β1, unlike to most other integrins, shows characteristic restricted expression in mesenchymal cells [61]. A comprehensive gene expression data for 150 primary cells from various tissues [62] reveals α8 subunit is selectively expressed on fibroblasts (Figure 4) [11]. Only α1, α8 and α11 subunit in all the 18 α and 8 β subunits of the integrin family show the fibroblast selective pattern, and α8 is most fibroblast selective as shown in Figure 4.…”

“…Furthermore, the fibroblast-selective expression of α8 is highly upregulated by a stimulus mimicking fibrosis. α8 in hepatic stellate cells (HSCs) either from rat or mouse is significantly induced both at the mRNA and protein levels [11] by culture activation for 14 days (Figure 5). HSCs are known to be activated by in vitro culture as in fibrotic tissue, associated with elevation of fibrosis markers such as α-smooth muscle actin (α-SMA).…”

“…However, many other members of the integrin family have not been examined each for aptitude to the therapeutic target and no reagents against αv-integrins has been approved for fibrosis and other diseases. We revisit the developmental history of αv-inhibitors, and show alternative new integrins, which contrastingly to αv-integrins exhibit pathology-specific expression in fibrosis, α8β1 [11] and α11β1 [12].…”