PROJECT SUMMARY
Immune signals profoundly influence brain physiology, and immune dysregulation is implicated in
neurodevelopmental disorders including autism, schizophrenia, as well as in the remodeling responses engaged
after brain injury. As such, there is a critical need to define the cells and molecules that mediate brain-immune
communication. Microglia, a type of glial cell, are the dominant immune cell in the brain parenchyma and play
key roles in synaptogenesis and synapse refinement during periods of brain remodeling. However, recent
discoveries have identified a rich array of immune cells in the meninges and perivascular barrier regions of the
brain. This raises the question of how these ‘border’ immune cells in and around the blood brain barrier impact
brain remodeling, including during development and after injury. In preliminary data, we demonstrate that a
subtype of immune cell known as group 2 innate lymphoid cells (ILC2s) expand and are activated in the
developing brain meninges and larger perivascular areas. They secrete their canonical effector cytokine
Interleukin-13 with a peak at postnatal days 5-12, which coincides with a robust period of synapse refinement.
During development, we show that genetic depletion of ILC2s impaired cortical inhibitory synapse function
consistent with defects in GABA receptor subunit composition. These mice had impacts in social recall memory
in adulthood. Importantly, global deletion of the IL-4/IL-13 receptor phenocopied these synaptic defects, whereas
exogenous IL-13 had the opposite effects. Aim 1 will determine the cellular targets and impacts of IL-13 signaling
that mediate these synaptic and behavioral effects in development, based on preliminary data showing that
microglia and border associated macrophages express high levels of the IL-13 receptor, and have transcriptional
and morphologic responses to IL-13. In preliminary data to Aim 2, we identify a stromal fibroblast niche where
ILC2s reside within the developing meninges and use single cell sequencing to define stromal ‘adventitial
fibroblasts’ that produce ILC2-supporting signals. We demonstrate that these fibroblasts are sufficient to support
ILC2 expansion in vitro, and that they produce the ILC2-regulating signals Interleukin-33. Aim 2 will determine
how the meningeal stromal niche supports ILC2 expansion and IL-13 production in vivo, including testing the
role of meningeal derived IL-33. In preliminary data to Aim 3, we find that meningeal ILC2s become reactivated
and expand after photothrombotic brain injury, limiting post-injury hyperexcitability and damage and promoting
the expansion of protective microglial subsets. Aim 3 will determine the impact of ILC2s, IL-13, and their
downstream targets in inhibitory synapse remodeling during injury recovery. We will test the alterations in the
meninges that sustain this ILC2 expansion and test the hypothesis that IL-33 signaling during damage is required
for these changes. Together, these studies will help to define how immune cells in the brain borders impact the
developing brain and how these may drive both beneficial and pathologic responses during development and
neuroinflammation.
