UBC Theses and Dissertations
Homeostasis of myeloid cells in the CNS and their roles in neuroinflammatory disease Ajami, Bahareh
A key regulator of central nervous system (CNS) inflammatory responses is a highly specialized subset of tissue macrophages that reside in the CNS parenchymal and perivascular spaces known as “microglia”. Microgliosis is a common response to multiple types of damage within the CNS and is commonly characterized by an increase in microglial cells. What remains elusive, however, is the origin of cells involved in this phenomenon and whether the increase in the number of cells is due to local expansion or recruitment of myeloid progenitors from the bloodstream. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of circulating myeloid cells recruitment under healthy conditions and in denervation or CNS neurodegenerative disease suggesting that microglia can respond to CNS trauma and degeneration by expanding in situ independently of the contribution of blood-derived myeloid precursors. Furthermore, I investigated the extent to which blood-derived myeloid cells contribute to the microglia population in conditions where other circulating blood-borne cells have access to the CNS, such as in multiple sclerosis, an autoimmune disease of CNS and its murine model experimental autoimmune encephalitis (EAE). Using a novel approach to specifically replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor-dependent recruitment of monocytes to the CNS blocked EAE progression suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, thus not ultimately contributing to the resident microglial pool. These findings collectively demonstrate that microglia constitute a unique myeloid cell population that are capable of long-term self-renewal within the CNS, and can respond to CNS trauma and degeneration by expanding in situ independently of the contribution of blood-derived myeloid precursors. Furthermore, two distinct subsets of myelomonocytic cells with unique roles in neuroinflammation and disease progression were identified under conditions where the blood-brain barrier is damaged and blood-derived leukocytes have access to the CNS parenchyma.
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