Role of host genetics in fibrosis

Abstract

Fibrosis can occur in tissues in response to a variety of stimuli. Following tissue injury, cells undergo transformation or activation from a quiescent to an activated state resulting in tissue remodelling. The fibrogenic process creates a tissue environment that allows inflammatory and matrix-producing cells to invade and proliferate. While this process is important for normal wound healing, chronicity can lead to impaired tissue structure and function.This review examines the major factors involved in transforming or activating tissues towards fibrosis. The role of genetic variation within individuals affected by fibrosis has not been well described and it is in this context that we have examined the mediators of remodelling, including transforming growth factor-beta, T helper 2 cytokines and matrix metalloproteinases.Finally we examine the role of Toll-like receptors in fibrosis. The inflammatory phenotype that precedes fibrosis has been associated with Toll-like receptor activation. This is particularly important when considering gastrointestinal and hepatic disease, where inappropriate Toll-like receptor signalling, in response to the local microbe-rich environment, is thought to play an important role.

Figure 1

Interleukin (IL)-13/transforming growth factor (TGF)-β signalling pathways. IL-13 signalling via IL-4Rα/IL-13Rα1 occurs via the JAK/STAT6 pathway and can cause increased collagen production from fibroblasts, recruit immune effector cells and enhance chemokine expression. Signalling via IL-13Rα2 in macrophages activates AP-1 inducing TGF-β secretion. Similarly IL-13Rα2 expression can be enhanced by TGF-β in hepatic stellate cells. TGF- β activates two serine/threonine kinase receptors and signals through Smad phosphorylation. TGF-β can also activate mitogen activated protein kinase signalling.

Figure 2

Signalling pathways triggered by TLR4 activation as a result of damage to the portal system. Altered barrier function resulting in increased bacterial translocation allows bacterial products including lipopolysaccharide (LPS) to activate hepatic stellate cells (HSCs) through Toll-like receptors (TLRs) (TLR4 shown as an example TLR). Activation of TLR4 through LPS binding initiates numerous signalling cascades which culminate in activation of transcription factors NF-κB and AP-1 and production of inflammatory cytokines/chemokines and immune mediators. This activation sensitises HSCs to the effects of transforming growth factor TGF-β which ultimately results in HSC activation and increased extracellular matrix/collagen production resulting in increased hepatic fibrosis.