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.