CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature
Antoine Louveau, Jasmin Herz, Maria Nordheim Alme, Andrea Francesca Salvador, Michael Q Dong, Kenneth E Viar, S Grace Herod, James Knopp, Joshua C Setliff, Alexander L Lupi, Sandro Da Mesquita, Elizabeth L Frost, Alban Gaultier, Tajie H Harris, Rui Cao, Song Hu, John R Lukens, Igor Smirnov, Christopher C Overall, Guillermo Oliver, Jonathan Kipnis, Antoine Louveau, Jasmin Herz, Maria Nordheim Alme, Andrea Francesca Salvador, Michael Q Dong, Kenneth E Viar, S Grace Herod, James Knopp, Joshua C Setliff, Alexander L Lupi, Sandro Da Mesquita, Elizabeth L Frost, Alban Gaultier, Tajie H Harris, Rui Cao, Song Hu, John R Lukens, Igor Smirnov, Christopher C Overall, Guillermo Oliver, Jonathan Kipnis
Abstract
Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
Conflict of interest statement
Competing interests: J.K. is an Advisor to PureTech Health/Ariya.
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References
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