Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

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.