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Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

Gadani, Sachin
Thesis/Dissertation; Online
Gadani, Sachin
Kipnis, Jonathan
Inflammation is a prominent feature of CNS injury that heavily influences neuronal survival, yet the signals that initiate and control it remain poorly understood. In this thesis I describe two linked projects that attempt to address this question. In the first, we identified the nuclear alarmin, interleukin (IL)-33, as an important regulator of the innate immune response after CNS injury. IL-33 is expressed widely throughout the healthy brain and is concentrated in white mater due to predominant expression in post-mitotic oligodendrocytes. IL-33 is released immediately after CNS injury from damaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment. Mice lacking IL-33 have impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site. In the second, we describes type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that is activated by IL-33 following CNS injury. ILC2s are present throughout the naïve mouse meninges, though are concentrated around the dural sinus, and have a unique transcriptional profile and sensitivity relative to lung ILC2s. After spinal cord injury, ILC2s are activated in an IL-33 dependent manner in the meninges and migrate into the lesion site. Finally, addition of ILC2s into the CSF of IL-33R –/– animals improves recovery following spinal cord injury. These results demonstrate a novel molecular and cellular mediators contributing to inflammation in the injured CNS and may lead to new therapeutic insights in CNS injury and neurodegenerative diseases.
University of Virginia, Department of Neuroscience, PHD (Doctor of Philosophy), 2016
Published Date
PHD (Doctor of Philosophy)
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