Abstract
Smoldering inflammation and neurodegeneration, primarily driven by intraparenchymal immune cell activation and glial dysfunction, remains a major therapeutic challenge in Multiple Sclerosis (MS) and contributes largely to disability progression. Current disease-modifying therapies effectively decrease relapse rate and, to a lesser extent, disease progression by targeting peripheral immune cells. However, they largely fail to address Central-Nervous-System-(CNS)-intrinsic pathological processes - especially glial dysfunction - thus leaving a critical gap relevant to disease progression and therapeutic intervention. In this context, neurotrophic factors (NTF) are secreted proteins central for development and maintenance of the CNS. They promote anti-inflammatory, protective phenotypes in astrocytes and microglia, support remyelination by enhancing oligodendrocyte precursor recruitment, maturation and survival, and exert direct neuroprotective effects. Exploring their role in MS offers a novel perspective on neuroimmune crosstalk and prevention of progressive neurodegeneration. In this article, we summarize relevant findings on NTFs in MS, and give an outlook on opportunities and challenges of using these mediators as next-generation disease-modifying therapies.