Border-Associated Macrophages in Parkinson's Disease

The immune system is very complex, made up of many different populations of specialized cells. Behaviors, surface features, and activities can be highly tissue specific. One can label a broad category of innate immune cells as macrophages, sharing common features, but even within a single tissue that class of macrophages can then be further subdivided by location and distinguishing features and actions. The ongoing discovery of important subpopulations of immune cells is a feature of research into inflammatory diseases. Here, researchers discuss the behavior of macrophages in Parkinson's disease, a condition in which chronic inflammation is thought to play an important role. The researchers provide evidence to suggest that it is macrophages bordering the brain, rather than the analogous microglia in the brain, that are producing disruptive, constant inflammatory signaling in response to the presence of the characteristic α-synuclein aggregation that is a biomarker of the condition.

Parkinson disease (PD) is the most common neurodegenerative movement disorder, characterized pathologically by the abnormal accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites and resulting in the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Due to activation of tissue-resident macrophages and the infiltration of both innate and adaptive immune cells, neuroinflammatory mechanisms have been strongly implicated in the neurodegeneration associated with α-syn accumulation.

Central nervous system (CNS) resident macrophages (CRMs) may be key antigen-presenting cells that orchestrate neuroinflammatory and neurodegenerative responses. CRMs include microglia in the parenchyma and border-associated macrophages (BAMs) that reside in the choroid plexus, dural and subdural meninges, and are adjacent to the vasculature within the perivascular space. It is important to note that BAMs have also been referred to as CNS-associated macrophages (CAMs) to highlight their anatomical location.

We found that 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.