Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases

Abstract

Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor β-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.

Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer

“…Some integrin receptors are strongly up‐regulated in CAFs, which by themselves produce high amounts of ECM, including collagens (18). Integrin targeting in myofibroblasts has been shown to inhibit fibrosis in multiple organs, such as liver, lung, and kidney (18, 27, 37, 38). Targeting to ITGA11 will be selective to a fibrotic disease or PDAC due to its absence or very low expression in other organs, as shown in our previous study in liver and lungs (27) and this study (kidneys, liver, skin, and small intestine).…”

The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis

“…Hence, these integrins play a minor role in tissue homeostasis but are instrumental during dynamic connective tissue remodeling, as occurring during fibrogenesis [84]. In fact, genetic inactivation of β1 [85] and depletion of α11 by a lentiviral sh-RNA approach [86] reduced HSC differentiation, migration, contractility and ECM production in vitro and allowed the identification of signaling pathways associated with α11β1 profibrotic functions. Interestingly, pharmacological inhibition of either pathway reduced collagen I expression in carbon tetrachloride (CCl 4 ) treated and bile duct ligated mice and in human liver slices ex vivo [85,86], suggesting that α11β1 plays a promoting role in hepatic fibrogenesis.…”

“…In fact, genetic inactivation of β1 [85] and depletion of α11 by a lentiviral sh-RNA approach [86] reduced HSC differentiation, migration, contractility and ECM production in vitro and allowed the identification of signaling pathways associated with α11β1 profibrotic functions. Interestingly, pharmacological inhibition of either pathway reduced collagen I expression in carbon tetrachloride (CCl 4 ) treated and bile duct ligated mice and in human liver slices ex vivo [85,86], suggesting that α11β1 plays a promoting role in hepatic fibrogenesis. Other collagen-binding β1-integrins, such as α1β1 or α2β1 are less well studied in the liver [84,87,88].…”

“…In addition, blocking integrin-linked signaling pathways may work as antifibrotic therapy: Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate, acts as a heterobivalent ligand for integrins and lysophospholipid receptor-1 and as such was able to induce lipid raft-mediated internalization of β1-integrin and subsequent inhibition of fibrogenic β1 signaling in vitro [198]. Bansal et al have demonstrated a link between α11-integrin and the hedgehog signaling pathway [86]. Inhibition of hedgehog by LDE225 has reduced fibrotic parameters and α11 expression in CCl 4 -treated mice and in human liver slices ex vivo [86].…”

Comprehensive network analysis of integrin α11 expressed in human breast cancer

“…ITGA11 is a member of the integrin family, which is involved in various processes that affect the biological behavior of cells, such as metastasis, embryogenesis, hemostasis, the immune response, tissue repair, cancer growth, tumor angiogenesis, and resistance to treatment [14,15]. However, its expression has been shown to be upregulated under malignant conditions, such as in non-small cell lung cancer, which has been suggested to be associated with cancer-cell growth [16,17].…”