Natural Killer Cells in Multiple Sclerosis: Dual Roles in Neuroinflammation and Neuroprotection

Multiple Sclerosis (MS) is a chronic, immune-mediated neurological disorder characterized by demyelination and neurodegeneration within the central nervous system (CNS). Among the diverse immune cells involved in the disease's pathophysiology, Natural Killer (NK) cells have garnered increasing interest due to their complex and seemingly contradictory roles. Traditionally recognized for their cytotoxic function against infected and transformed cells, NK cells are now understood to exert both pro-inflammatory and regulatory effects in MS. This review explores the dual roles of NK cells in MS, highlighting their contribution to neuroinflammation and potential in mediating neuroprotection. On one hand, NK cells can exacerbate disease activity by promoting the destruction of oligodendrocytes and releasing inflammatory cytokines such as IFN-γ and TNF-α. On the other hand, subsets of NK cells particularly the CD56^bright population—demonstrate immunoregulatory properties by modulating dendritic cell function and suppressing autoreactive T cells, thereby contributing to CNS immune homeostasis. We also discuss how NK cell frequency, phenotype, and function are altered in MS patients, and how current disease-modifying therapies impact these cells. Understanding the conditions under which NK cells shift from pathogenic to protective roles may unlock new therapeutic avenues aimed at enhancing their regulatory capacity while minimizing their harmful effects. Ultimately, targeting NK cell responses holds promise for more precise immunomodulation in MS, potentially balancing disease control with CNS preservation.