Glia–glia crosstalk via semaphorins: Emerging implications in neurodegeneration

The central nervous system (CNS) is wired by a complex network of integrated glial and neuronal signals, which is critical for its development and homeostasis. In this context, glia-glia communication is a complex and dynamic process that is essential for ensuring optimal CNS function. Semaphorins, which include secreted and transmembrane molecules, and their receptors, mainly found in the plexin and neuropilin families, are expressed in a wide range of cell types, including glia. In the CNS, semaphorin signalling is involved in a spectrum of processes, including neurogenesis, neuronal migration and wiring, and glial cell recruitment. Recently, semaphorins and plexins have attracted intense research aimed at elucidating their roles in instructing glial cell behavior during development or in response to inflammatory stimuli. In this review, we provide an overview of the multifaceted role of semaphorins in glia–glia communication, highlighting recent discoveries about semaphoring-dependent regulation of glia functions in healthy conditions. We also discuss the mechanisms of gliaglia crosstalk mediated by semaphorins under pathological conditions, and how these interactions may provide potential avenues for therapeutic intervention in neuroinflammation-mediated neurodegeneration.