TAM Receptor Signalling and Demyelination

Abstract

The TAM family (Tyro3, Axl and Mer) of receptor protein tyrosine kinases play pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. These processes are central to both the initial development and pathological course of human multiple sclerosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS), including in oligodendrocytes, the myelin-producing cell of the CNS. Recent studies have shown that Gas6-dependent TAM receptor signalling is an important modulator of oligodendrocyte survival and microglial phenotype both in vitro and in vivo. Multiple lines of evidence allow us to hypothesise that, during a demyelinating challenge, dysfunctional TAM receptor signalling could lead to a ‘vicious cycle’ of cell death, reduced phagocytosis and deleterious immune hyper-activation. A current challenge in this field is to expand our understanding of TAM receptor signalling from rodent models of central demyelination to human disease.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

“…The MerTK pathway has been implicated in myelin clearance in the cuprizone toxin demyelination model. In this model, Gas6 2/2 mice show increased microglial number and greater demyelination and inflammatory activity compared with wild-type animals, consistent with the ability of Gas6 to modulate microglial activation (35,36). In addition, direct administration of recombinant human Gas6 into the CNS in this model resulted in enhanced debris clearance, remyelination, and axonal survival (37).…”

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

“…Tyro3 is highly expressed in the central nervous system (CNS), and Axl and Mer expression is more restricted and occurs at a lower level than Tyro3 [12].…”

“…Gas6 and Protein S possess 1 Gla domain, 4 epidermal growth factor (EGF)-like domains and 2 laminin-G (LG) domains at the N-terminus. Both ligands are dependent on vitamin K for post-translational modification of the Gla domain [12]. The Gla domain is a binding site for phospholipids on the surface of cell membranes.…”

“…The relative affinity of Gas6 is Axl>Tyro3>Mer, and Gas6 is the sole ligand for Axl [13]. Protein S is a ligand for the Mer and Tyro3 receptors, but not the Axl receptor [12]. Other neurotrophic factors may also regulate TAM receptors.…”

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

“…A well-known example is phosphatidylserine (PS) when translocated to the outer leaflet of a plama membrane and binding the soluble Gas6 protein (for 'growth arrest-specific gene 6') ( Figure 1). The resulting PS-Gas6 cluster is a ligand for a triad of protein-tyrosine kinase receptors, termed TAM-receptors (Tyro3, Axl, Mer), which are expressed on microglia/macrophages and trigger phagocytosis (Binder and Kilpatrick, 2009). Genetically inactivating the Axl receptor, a protein upregulated on microglia during cuprizone treatment, prevents microgliosis and delays the generation of myelin debris and its clearance in mutant mice (Hoehn et al, 2008).…”