Stress-induced tunneling nanotube communication in CNS glial cells: implications for inflammatory demyelination and repair failure

Multiple sclerosis and related inflammatory demyelinating disorders of the central nervous system, including neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease, are characterized by immune-mediated tissue injury, glial dysfunction, metabolic stress, and incomplete repair. Although peripheral immune infiltration and antibody-mediated mechanisms explain many aspects of acute lesion formation, they do not fully account for persistent lesion activity, metabolic instability, or remyelination failure within the local tissue microenvironment. Tunneling nanotubes are thin, actin-rich membranous connections that enable direct intercellular transfer of organelles, vesicles, proteins, ions, and stress-related cargoes. In the nervous system, tunneling nanotube-mediated communication has been implicated in mitochondrial transfer, glial-neuronal interactions, pathological cargo dissemination, and cellular stress adaptation. This review examines the potential role of tunneling nanotubes in multiple sclerosis and related inflammatory demyelinating disorders from a lesion-centered perspective. Moving beyond general descriptions of TNT biology, glial communication, and mitochondrial transfer, we consider how TNT-mediated intercellular exchange may intersect with pathological cargo transfer, metabolic stress and support, neurovascular dysfunction, and impaired repair within demyelinating lesions. In multiple sclerosis, they may be particularly relevant to chronic active lesion edges, glial stress responses, and remyelination failure. In aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder, they may be more closely related to astrocytic injury and neurovascular-unit stress. In myelin oligodendrocyte glycoprotein antibody-associated disease, their potential relevance is more speculative and may lie in post-inflammatory repair coordination. Direct evidence remains limited. Future studies should prioritize rigorous in situ identification, cell-type-specific analysis, cargo tracking, and causal intervention experiments before tunneling nanotubes can be considered a validated disease mechanism.