Age-related demyelination and neurodegeneration susceptibility associates with meningeal neutrophil accumulation in a murine model of multiple sclerosis

People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils. Overall design: We performed scRNAseq (CITE-seq) to understand transcriptional states of immune cells in the meninges of young and old SJL/J mice at D11 post induction of EAE. Naïve SJL/J Young mouse: TotalSeq B Hashtag 1 ACCCACCAGTAAGAC Naïve SJL/J Old mouse: TotalSeq B Hashtag 2 GGTCGAGAGCATTCA EAE SJL/J Young mouse: TotalSeq B Hashtag 3 CTTGCCGCATGTCAT EAE SJL/J Old mouse: TotalSeq B Hashtag 4 AAAGCATTCTTCACG All mice: Anti-PE barcode TGACCAGTTCCGCAT