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Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
Published October 16, 2022
Output Details
Preprint May 23, 2023
Published October 16, 2022
Description
Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.
Identifier (DOI)
10.1038/s41467-023-39060-w