Meningeal lymphatics orchestrate vertebral neutrophils via a Hex1Cer-NETs axis to promote autoimmune neuroinflammation

Abstract

Abstract Meningeal enhancement is observed on cranial and spinal magnetic resonance image in a subset of patients with multiple sclerosis (MS) and is associated with a higher risk of future disease progression, however, the underlying mechanisms by which it promotes such progression remain elusive. By cross-validating clinical MRI datasets with the experimental autoimmune encephalomyelitis model (EAE), we revealed a meningeal lymphatics-innate immune axis that orchestrates a localized signaling cascade driving and promoting the pathogenesis of inflammatory demyelination. We show that the earliest phase of the disease is characterized by a rapid, selective influx of neutrophils recruited directly from the vertebral bone marrow via specialized osteo-channels. Crucially, we identify the glycosphingolipid hexosylceramide (Hex1Cer), which is derived from meningeal lymphatic vessels after drainage of myelin debris and triggers neutrophil extracellular trap (NET) formation. These meningeal NETs utilized a SELPLG-SELL axis to recruit pathogenic lymphocytes, promoting their infiltration into the spinal cord parenchyma. Both pharmacological targeting of the Hex1Cer or NETs formation pathway significantly reduced downstream T cell infiltration and clinical severity. Finally, we demonstrate that low-dose intrathecal repurposing of Sivelestat to target this meningeal niche provides superior protection compared to systemic delivery. Our findings define the meningeal lymphatic endothelial cells (mLECs) as active metabolic gatekeepers of neuroinflammation and establish the mLEC-myelin-Hex1Cer-NETs formation axis as a high-priority therapeutic target for intercepting MS.