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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Central Nervous System / immunology
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Central Nervous System / pathology
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Dendritic Cells / pathology
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Disease Models, Animal
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Encephalitis / chemically induced
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Encephalitis / pathology*
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Encephalitis / physiopathology*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Lymph Nodes / pathology
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Lymphatic Vessels / physiology*
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Male
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Meninges / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Myelin-Oligodendrocyte Glycoprotein / toxicity
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Peptide Fragments / toxicity
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Photosensitizing Agents / pharmacology
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Receptors, CCR7 / deficiency
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Receptors, CCR7 / genetics
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Spleen / pathology
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T-Lymphocytes / physiology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antigens, CD
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Ccr7 protein, mouse
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Homeodomain Proteins
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MicroRNAs
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Photosensitizing Agents
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Receptors, CCR7
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Tumor Suppressor Proteins
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myelin oligodendrocyte glycoprotein (35-55)
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prospero-related homeobox 1 protein
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Green Fluorescent Proteins