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

Abstract

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of PD pathogenesis. Neuroinflammation specifically induced by α-syn has been shown to exacerbate neurodegeneration, yet the role of 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-syn related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response. Surprisingly, the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-syn expression led to an expansion in BAM numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that BAMs played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, BAMs were identified in post-mortem PD brain in close proximity to T cells. These results point to a critical role for BAMs in mediating PD pathogenesis through their essential role in the orchestration of the α-syn-mediated neuroinflammatory response.

The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra

“…MRC1 is important for myeloid plasticity and adaptive immune responses 122 , monocytes/BAMs, and, in activated microglia/myeloid cells, can be a marker of activation 123,124 . Significantly, monocytes/BAMs (high expression levels of CD163 and MRC1 ) have recently been shown to be necessary for an alpha-synuclein-induced neurodegeneration in a mouse model of PD 125 . The interaction between T-cells and these monocytes/BAMs via MRC1-PTPRC is consistent with previous reports 5,125 identifying increased colocalization of both cell-types around blood vessels in postmortem PD.…”

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology

“…The complex and multi-dimensional macrophage response to PFFs and synucleinopathy Macrophages such as microglia can adopt a multitude of states and phenotypes in different neurodegenerative diseases 55 . In PD specifically, several groups have shown that microglia or other CNS-associated macrophages engage in T-cell recruitment 35,56 and inflammasome activation [57][58][59] to drive neurodegeneration. A previous study found upregulation of multiple proinflammatory cytokines in the gut 7 days following PFF injection 18 , suggesting that perhaps ENS macrophages engage a similar pro-inflammatory program to microglia in response to α-syn.…”

“…CNS-resident macrophages have been shown to engage in both beneficial and detrimental functions during neurodegenerative diseases and represent promising targets for new therapies [31][32][33] . Prominent examples include activating the adaptive immune response, which can lead to neuronal death [34][35][36] , and microglia-mediated complement-dependent synaptic pruning [37][38][39][40] , which mechanistically links protein aggregates to neuronal dysfunction. Given the range of states macrophages can adopt, and the disease-modifying potential of macrophage phenotype, it is important to elucidate the precise response of ENS macrophages to synucleinopathy and how this response contributes to development and/or progression of the disease process.…”

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

“…Interesting, at this timepoint reduced CD163-immunoreactivity was found in the lesioned hemisphere by IHC. Expression of CD163 in the brain has been associated with border associated macrophages, which have been identified as the driving cells for immune cell recruitment and infiltration (56). Since we only evaluated CD163 expresssion at 8 weeks, it is possible that we missed a significant increase in this glycoprotein.…”