Microglia orchestrate neuroinflammation

Abstract

Experiments in genetically altered mice reveal that microglia play an important role in the neurological damage associated with neuro-nopathic Gaucher disease.

Keywords: Gaucher disease; Gba1; NK cells; human; lipids; medicine; microglia; mouse; neuroinflammation.

Figure 1.. Role of elevated glucosphingolipids and activated microglia in neuronopathic Gaucher disease.

(A) In the brains of neuronopathic Gaucher disease mice are multiple interacting cell types, including neurons (green outline), astrocytes (purple outline), microglia (red outline), and immune cells from the blood, such as macrophages (grey), NK cells (blue circles), and cytotoxic lymphocytes (orange circles). Neuronopathic Gaucher disease mice, which lack the Gba1 gene, have higher levels of glucosylceramide and glucosylsphingosine. Elevation of these glucosphingolipids deregulates the interactions (black arrows) between neurons, microglia, astrocytes and macrophages, causing the immune cells to release inflammatory cytokines such as IFN-γ and Pro-IL-1β. The resulting inflammatory environment leads to neuronal injury and death. Injured neurons release the biomarker Nf-L, and there are also higher levels of the lipoprotein ApoE and certain lipids (such as hexosylceramides and lysophosphatidylcholine), which are released into the blood where they can be detected. (B) Selective rescue of Gba1 expression in the microglia of neuronopathic Gaucher disease mice reduced the influx of blood-derived immune cells, and the immune activity of macrophages and astrocytes. This decreased the levels of inflammatory cytokines, resulting in less neuronal injury and lower levels of the biomarkers Nf-L, ApoE, and lipids. (C) Substrate reduction therapy (SRT) using a drug that blocks the synthesis of glucosylceramide is approved to treat patients with type 1 Gaucher disease. When mice with Gba1 expression restored in their microglia were treated with a brain-permeable SRT drug, the level of glucosphingolipids and neuroinflammation was reduced even further, along with a decrease in the levels of Nf-L, ApoE and lipid biomarkers. GluCer, glucosylceramide; GluSph, glucosylsphingosine; Nf-L, neurofilament light chain; ApoE, apolipoprotein E; IFN-γ,Interferon gamma; Pro-IL-1-β, Pro-Interleukin 1 beta.