Detrimental roles of innate immune cells in neuromyelitis optica spectrum disorder: Pathogenesis and therapeutic targeting.

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects the optic nerves, spinal cord, and brainstem, leading to severe relapses and potentially significant neurological disability. Most NMOSD patients present with anti-aquaporin-4 autoantibodies (AQP4-IgG), which trigger acute neuroinflammation and astrocyte damage through classical complement pathway activation and immune cell recruitment, yet AQP4-IgG alone does not fully account for NMOSD pathogenesis, suggesting additional contributing mechanisms. Emerging evidence highlights the critical role of innate immune cells-macrophages, neutrophils, eosinophils, and natural killer cells-in NMOSD lesion development, in which they amplify inflammation through cytokine release, antibody-dependent cellular cytotoxicity, and immune cell recruitment, ultimately exacerbating CNS damage. Importantly, recent advancements in NMOSD therapies have incorporated targeting innate immune responses, including interleukin-6 and complement inhibitors, and neutrophil and eosinophil modulators, enhancing treatment efficacy. This review explores the multifaceted roles of innate immune cells, their interactions with AQP4-IgG, and their contribution to disease progression. In summary, targeting innate immune pathways offers an alternative strategy to mitigate inflammation and damage in CNS.