Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease in which many patients experience a relapsing-remitting syndrome which cumulates in a progressive neurodegeneration. Despite effective therapies that mitigate flares, disability accumulation continues to occur, likely due to chronic inflammatory lesions. Central nervous system (CNS)-resident macrophages are the primary immune cells that remain activated in these chronic lesions and are strongly implicated in the pathogenesis across multiple neurodegenerative disease; however, the mechanisms by which they contribute to chronic, degenerative disease in MS remain unclear. Elucidating these mechanisms would not only improve understanding of their role in disease but should also aid in the development of therapies that specifically target degeneration. Here, I evaluated the role of chemoreceptor, MS4A6A, and its murine ortholog, Ms4a6c, in animal and in vitro models of MS. Genetic knockout of Ms4a6c results in the downregulation of activation markers, such as CLEC7A, and T-cell-co-stimulatory proteins, such as MHCII and CD86, in both peripheral and central macrophages leading to reduced autoreactivity of pathogenic T cells and mitigated disease phenotypes. These results suggest that inhibiting MS4A6A/6c might be useful as a therapeutic approach for combating neurodegeneration in MS. To investigate this possibility further, I identified and characterized the potential of a small molecule drug to inhibit MS4A6A and Ms4a6c pharmacologically. I discovered that this drug reduced the activation state of CNS macrophages and mitigated disease phenotypes. This work characterizes an important role of MS4A6A in macrophages in progressive MS and proposes a promising novel treatment strategy to reduce progressive degeneration.