Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Abstract

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

Keywords: Axl; Gas6; IPF; MerTK; TAM; cirrhosis; fibrosis; inflammation.

Figure 1

A potential model of Gas6/TAM activity in the case of acute and chronic injury. (A) A cell exposed to a damage overexpressing Gas6/TAM receptors. The arrow pointing upward means increasing. Down arrow means decreasing. The system exerts its anti-inflammatory activities: efferocytosis, switch-off of IFN signature, and downregulation of inflammatory cytokines expression. This contributes to self-limitation of inflammatory response. (B) The overexpression of Gas6/TAM receptors induced by chronic exposition to a stressor, leading to the production and release of extracellular matrix, ultimately contributing to fibrosis development.