Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

• Published in: Nature communications Vol. 14; no. 1; pp. 3754 - 16
• Main Authors: Schonhoff, A. M., Figge, D. A., Williams, G. P., Jurkuvenaite, A., Gallups, N. J., Childers, G. M., Webster, J. M., Standaert, D. G., Goldman, J. E., Harms, A. S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/19; 14/35; 14/63; 38/91; 631/378/1689; 631/378/2596; 631/378/371; 64/60; alpha-Synuclein - metabolism; Antigen presentation; Antigen-presenting cells; Antigens; CD4 antigen; Central nervous system; Combinatorial analysis; Dopamine receptors; Gene sequencing; Humanities and Social Sciences; Humans; Immune system; Infiltration; Inflammation; Inflammation - pathology; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Microglia; Microglia - metabolism; Movement disorders; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Neuroinflammatory Diseases; Parkinson Disease - metabolism; Parkinson's disease; Pathogenesis; Science; Science (multidisciplinary); Synuclein
• DOI: 10.1038/s41467-023-39060-w
• ISSN: 2041-1723

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. Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the α-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.