Role of meningeal lymphatic drainage in CSF1R-related leukoencephalopathy

About This Grant

ABSTRACT Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a devastating genetic neurodegenerative disease characterized by abnormal glial responses, marked white matter pathology in the brain, and severe motor and cognitive symptoms. Currently, there are no effective therapies against CSF1R- related leukoencephalopathy, and its etiology remains poorly understood. Despite the limited consensus regarding its underlying cellular mediators and mechanisms, CSF1R loss-of-function and deficient microglial function are thought to contribute to the disease pathogenesis. However, little is known about the immune changes at the border tissues of the brain, namely at the meninges, and how changes in meningeal immunity and lymphatic drainage might contribute to the initiation and progression of brain pathology in CSF1R- related leukoencephalopathy. Unexpectedly, our preliminary data shows a decrease of lymphatic vessels in the dura of the established model of CSF1R-related leukoencephalopathy (Csf1r+/- mice) and the Fms-intronic regulatory element (FIRE) knockout mice (Csf1rΔFIRE/ΔFIRE), a new mouse model of CSF1R- related leukoencephalopathy. We hypothesize that a deleterious innate immune response at the brain-meningeal interface might affect the pathophysiology of CSF1R- related leukoencephalopathy by dampening lymphatic drainage of the CNS. In this project, we will use the Csf1rΔFIRE/ΔFIRE mouse model to further explore the changes in the central nervous system (CNS) associated immune cells, namely in meningeal myeloid cells, and its association with impaired lymphatic drainage of the brain. I will determine the cellular mechanisms and immune mediators linked to the absence of meningeal lymphatic vasculature in Csf1rΔFIRE/ΔFIRE mice (Aim 1). Secondly, I will use different experimental approaches to enhance meningeal lymphatic drainage in Csf1rΔFIRE/ΔFIRE mice and determine its therapeutic impact on exacerbated glial activation, white matter degeneration, and behavior deficits (Aim 2). This proposal will establish whether impaired meningeal lymphatic vasculature represents a previously unappreciated pathological phenomenon, and a potential therapeutic target, in CSF1R-related leukoencephalopathy.