αv integrins: key regulators of tissue fibrosis

Abstract

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction and eventual organ failure. Therefore, the development of effective anti-fibrotic therapies is urgently required. During fibrogenesis, complex interplay occurs between cellular and extracellular matrix components of the wound healing response. Integrins, a family of transmembrane cell adhesion molecules, play a key role in mediating intercellular and cell-matrix interactions. Thus, integrins provide a major node of communication between the extracellular matrix, inflammatory cells, fibroblasts and parenchymal cells and, as such, are intimately involved in the initiation, maintenance and resolution of tissue fibrosis. Modulation of members of the αv integrin family has exhibited profound effects on fibrosis in multiple organs and disease states. In this review, we discuss the current knowledge of the mechanisms of αv-integrin-mediated regulation of fibrogenesis and show that the therapeutic targeting of specific αv integrins represents a promising avenue to treat patients with a broad range of fibrotic diseases.

Keywords: Extracellular matrix; Fibrosis; Integrins; Myofibroblasts; TGFβ.

Fig. 1

Complex interplay of αv-integrin-mediated regulation of tissue fibrosis. αv integrins (β1, β3, β5, β8) expressed on fibroblasts and αvβ6 expressed on epithelia activate transforming growth factor beta (TGFβ) through their interaction with a linear arginine-glycine-aspartic acid (RGD) binding motif present on the latency-associated peptide (LAP) in the extracellular matrix (ECM). TGFβ released from the ECM by injured epithelia might directly signal to the myofibroblast to promote further ECM production. Furthermore, αv integrins on myofibroblasts can release active TGFβ from the ECM; this TGFβ then signals in an autocrine manner to drive further ECM production by myofibroblasts