Traumatic CNS injuries and many neurodegenerative diseases result in the continuous death of neurons. This spread of neuronal death is termed secondary neurodegeneration. Several works over the last two decades have demonstrated the role of the immune system in affecting secondary degeneration. While some subsets of T cells and macrophages are limiting the spread of damage and thus contributing to neuroprotection, others are perpetuating neurodegeneration. Our goal is to better understand what subsets of T cells mediate neuroprotection and what molecular cues recruit these T cells to the site of injury. The ultimate goal is to intervene with this process and boost neuroprotective immunity. We have recently demonstrated a role for both effector and regulatory CD4+ T cells in response to CNS injury. We also showed that neuroprotective T cells, through their production of IL-4, limit the degree of secondary degeneration; however, the precise cellular targets of IL-4-mediated neuroprotection have not been identified to date. Activation of T cells after CNS injury takes place in the CNS-draining deep cervical lymph nodes (dCLNs), and surgical resection of dCLNs results in impaired neuronal survival after CNS injury. Although the connection between cerebrospinal fluid (CSF) and the dCLNs has been appreciated, the exact path of cell trafficking between the two regions was not completely understood. In search for the routes of cell entry and exit to/from the CNS, we serendipitously discovered classical lymphatic vessels in the brain meninges located along the dural sinuses, which carry lymphocytes and myeloid cells and drain CSF and immune cells directly to the dCLNs. Characterization of these vessels may allow us to gain a control over drainage of cellular and soluble CSF constituents and thus possibly alter the immune response to brain antigens. The overarching hypothesis that we aim to address in this proposal is that meningeal lymphatic vessels regulate immune response to CNS injury within the meningeal spaces and the recruited T cells acquire there a Th2 phenotype prior to their entry into the site of injury. Th2 skew and a subsequent IL-4 production mediate neuroprotection at the site of injury. The three specific aims to be addressed in this proposal are: (1) To test th hypothesis that meningeal lymphatic vessels are regulating post-injury meningeal T cell immunity; (2) To test the hypothesis that the combined action of oligodendrocyte-derived IL-33 and ILC2-derived IL-13, skew meningeal T cells to Th2; (3) To define the cellular targets of IL-4-mediated neuroprotection. A successful completion of the aims of this proposal will enhance our understanding of the molecular events that drive a protective immune response after CNS injury and will shed a light on new therapeutic targets for CNS injuries and other neurodegenerative disorders.
Traumatic CNS injuries and many neurodegenerative diseases result in the continuous death of neurons, in which the immune system is playing a central role. While some subsets of immune cells are limiting the spread of damage, others are perpetuating neurodegeneration. Our goal is to eventually intervene with this process and boost neuroprotective immunity while limiting the neurodestructive response. A successful completion of this proposal will enhance our understanding of the molecular events that drive a protective immune response after CNS injury and will bring to light new therapeutic targets for CNS injuries and other neurodegenerative disorders.
|Louveau, Antoine; Herz, Jasmin; Alme, Maria Nordheim et al. (2018) CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci 21:1380-1391|
|Norris, Geoffrey T; Smirnov, Igor; Filiano, Anthony J et al. (2018) Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury. J Exp Med 215:1789-1801|
|Louveau, Antoine; Filiano, Anthony J; Kipnis, Jonathan (2018) Meningeal whole mount preparation and characterization of neural cells by flow cytometry. Curr Protoc Immunol 121:|
|Kipnis, Jonathan (2018) Immune system: The ""seventh sense"". J Exp Med 215:397-398|
|Louveau, Antoine; Plog, Benjamin A; Antila, Salli et al. (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127:3210-3219|
|Herz, Jasmin; Filiano, Anthony J; Smith, Ashtyn et al. (2017) Myeloid Cells in the Central Nervous System. Immunity 46:943-956|
|Gadani, Sachin P; Smirnov, Igor; Smith, Ashtyn T et al. (2017) Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. J Exp Med 214:285-296|
|Filiano, Anthony J; Gadani, Sachin P; Kipnis, Jonathan (2017) How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci 18:375-384|
|Kipnis, Jonathan (2016) Multifaceted interactions between adaptive immunity and the central nervous system. Science 353:766-71|
|Louveau, Antoine; Da Mesquita, Sandro; Kipnis, Jonathan (2016) Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease? Neuron 91:957-973|
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