Could Gas6/TAM Axis Provide Valuable Insights into the Pathogenesis of Systemic Sclerosis?

Abstract

Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular injury, extracellular matrix deposition, autoimmunity, inflammation, and fibrosis. The clinical complexity and high heterogeneity of the disease make the discovery of potential therapeutic targets difficult. However, the recent progress in the comprehension of its pathogenesis is encouraging. Growth Arrest-Specific 6 (Gas6) and Tyro3, Axl, and MerTK (TAM) receptors are involved in multiple biological processes, including modulation of the immune response, phagocytosis, apoptosis, fibrosis, inflammation, cancer development, and autoimmune disorders. In the present manuscript, we review the current evidence regarding SSc pathogenesis and the role of the Gas6/TAM system in several human diseases, suggesting its likely contribution in SSc and highlighting areas where further research is necessary to fully comprehend the role of TAM receptors in this condition. Indeed, understanding the involvement of TAM receptors in SSc, which is currently unknown, could provide valuable insights for novel potential therapeutic targets.

Keywords: Gas6; TAM receptors; biomarkers; systemic sclerosis.

Figure 1

Pathogenetic mechanisms involved in SSc. Endothelial cells are activated upon vascular damage with the consequent expression of adhesion molecules and production of vWF, ET-1, and chemokines. The injured endothelium produces molecules capable of recruiting immune cells. Inflammatory infiltrates composed of monocytes, macrophages, and T cells and B cells sustain the release of proinflammatory and profibrotic cytokines. Resident fibroblasts undergo a phenotypic conversion to myofibroblasts, the effector cells of fibrosis. Abbreviation: vascular cell adhesion molecule-1, VCAM-1; intercellular cell adhesion molecule-1, ICAM-1; endothelin-1, ET-1; B cell activating factor, BAFF; interleukin, IL; tumor necrosis factor, TNF; Transforming Growth Factor-β, TGF-β; Von Willebrand factor, vWF; endothelial cell, ECs.

Figure 2

Structure of TAMs (A). TAMs consist of immunoglobulin-like (IgL) domains, two fibronectin domains, and a kinase domain. Structure of Gas6 (B). Gas6 consists of a gamma-carboxyglutamic acid (Gla) domain, four epidermal growth factor (EGF)-like domains, and two laminin G (LG)-like domains. Created with https://www.BioRender.com (accessed on 18 June 2024).