Notch: A new player in MS mechanisms

Abstract 

Notch is a family of four transmembrane receptors (Notch1–4) that orchestrate differentiation of various cell types, tissues and organs. Recent studies have revealed that Notch, among other processes, regulates immune responses of peripheral T cells, controls oligodendrocyte maturation and myelination of axons and under inflammatory conditions affects activation of macrophages and microglia. Therefore, Notch signaling has been implicated in the differentiation and function of all cell types considered crucial for the development and clinical progression of multiple sclerosis (MS). Importantly, inflammatory/demyelinating lesions in MS and its animal model, autoimmune experimental encephalomyelitis (EAE), abundantly express Notch receptors, their ligands and downstream activation targets. In EAE, in vivo modulation of Notch signaling affects immune responses of myelin-reactive T cells, enhances tissue repair and reduces clinical severity of the disease. In this review, we present recent findings on how Notch signaling may affect function of both immune and glial cells, analyze data implicating the Notch pathway in MS and EAE, and discuss the therapeutic potential of manipulating Notch signaling in MS patients.

Keywords: Multiple sclerosis, Remyelination, Autoimmunity, Notch, Gamma-secretase inhibitors