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Research Article: Repulsive guidance molecule-a regulates neutrophil-associated Th17 responses in CNS autoimmunity

Date Published: 2026-08-19

Abstract:
Repulsive guidance molecule-A (RGMa) is well-known for its roles in T-cell-mediated neuroinflammation and CNS repair. Innate-adaptive immune interactions, particularly between neutrophils and Th17 cells, are emerging as critical drivers of neuroinflammatory pathology in multiple sclerosis (MS). Whether RGMa regulates these neutrophil-associated Th17 responses remains largely unknown. Elucidating this mechanism may reveal novel therapeutic targets for MS. Serum levels of RGMa, BMP4, neutrophil elastase (NE), IL-17A, and inflammatory markers were measured in 10 relapsing-remitting MS patients during acute relapse and remission phases, and in 10 healthy controls. In vitro transwell co-cultures using primary human neutrophils and CD3 + T cells were employed to evaluate the effects of RGMa monoclonal antibody (RGMa-mAb) treatment on neutrophil activation, Th17-associated responses, and T-cell migration. In parallel, experimental autoimmune encephalomyelitis (EAE) mice were treated with RGMa-mAb to assess neuroinflammation and BMP4-SMAD-related signaling changes in vivo . Serum RGMa and NE were elevated in acute-phase MS patients versus both remission and healthy controls ( p < 0.05), whereas IL-17A was elevated versus healthy controls ( p < 0.05). Correlation analyses showed that RGMa levels were positively associated with the neutrophil activation marker NE ( r = 0.71), while serum Ly6G6D levels were correlated with IL-17A levels ( r = 0.66), suggesting a potential link between neutrophil-associated inflammatory responses and Th17 activation during active disease. In vitro , RGMa-mAb treatment attenuated PMA-induced neutrophil activation, reduced Th17-associated inflammatory responses, and suppressed T-cell migration in the co-culture system. In EAE mice, RGMa-mAb ameliorated neurological deficits, decreased neutrophil- and Th17-associated inflammatory markers, and modulated BMP4-SMAD signaling. RGMa contributes to neutrophil-associated Th17 inflammatory responses in CNS autoimmunity, potentially in association with BMP4-SMAD signaling. Targeting RGMa may therefore represent a potential therapeutic strategy for MS-associated neuroinflammation that warrants further investigation.

Introduction:
Repulsive guidance molecule-A (RGMa) is well-known for its roles in T-cell-mediated neuroinflammation and CNS repair. Innate-adaptive immune interactions, particularly between neutrophils and Th17 cells, are emerging as critical drivers of neuroinflammatory pathology in multiple sclerosis (MS). Whether RGMa regulates these neutrophil-associated Th17 responses remains largely unknown. Elucidating this mechanism may reveal novel therapeutic targets for MS.

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