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CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature

Louveau, A;Herz, J;Alme, MN;Salvador, AF;Dong, MQ;Viar, KE;Herod, SG;Knopp, J;Setliff, JC;Lupi, AL;Da Mesquita, S;Frost, EL;Gaultier, A;Harris, TH;Cao, R;Hu, S;Lukens, JR;Smirnov, I;Overall, CC;Oliver, G;Kipnis, J;

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.