Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration

Organized meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the...

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Bibliographic Details
Published in:	Brain (London, England : 1878) Vol. 145; no. 12; pp. 4287 - 4307
Main Authors:	James Bates, Rachel E, Browne, Eleanor, Schalks, Renee, Jacobs, Heather, Tan, Li, Parekh, Puja, Magliozzi, Roberta, Calabrese, Massimiliano, Mazarakis, Nicholas D, Reynolds, Richard
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 19-12-2022
Subjects:	Animals Cerebral Cortex - pathology Immunologic Factors - metabolism Inflammation - pathology Lymphoid Tissue - metabolism Lymphoid Tissue - pathology Lymphotoxin-alpha - metabolism Meninges Multiple Sclerosis - pathology Multiple Sclerosis, Chronic Progressive - pathology Myelin-Oligodendrocyte Glycoprotein Original Rats neurodegeneration inflammation demyelination multiple sclerosis meninges
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Summary:	Organized meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the CSF of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of lymphotoxin-alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology. Stereotaxic injections of recombinant lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and subpial demyelination that resolved after 28 days, with demyelination being dependent on prior subclinical immunization with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localized overexpression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin + fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial and astroglial activation, subpial demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial demyelination was partially dependent on previous myelin oligodendrocyte glycoprotein immunization, the neuronal loss was present irrespective of immunization. Conditioned medium from LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive multiple sclerosis brain.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Rachel E James Bates and Eleanor Browne contributed equally to this work.
ISSN:	0006-8950 1460-2156
DOI:	10.1093/brain/awac232