Brain inflammation triggers macrophage invasion across the blood-brain barrier in Drosophila during pupal stages

Abstract

The nervous system is shielded from circulating immune cells by the blood-brain barrier (BBB). During infections and autoimmune diseases, macrophages can enter the brain where they participate in pathogen elimination but can also cause tissue damage. Here, we establish a Drosophila model to study macrophage invasion into the inflamed brain. We show that the immune deficiency (Imd) pathway, but not the Toll pathway, is responsible for attraction and invasion of hemolymph-borne macrophages across the BBB during pupal stages. Macrophage recruitment is mediated by glial, but not neuronal, induction of the Imd pathway through expression of Pvf2. Within the brain, macrophages can phagocytose synaptic material and reduce locomotor abilities and longevity. Similarly, we show that central nervous system infection by group B Streptococcus elicits macrophage recruitment in an Imd-dependent manner. This suggests that evolutionarily conserved inflammatory responses require a delicate balance between beneficial and detrimental activities.

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…ApoE also promotes neutrophil activation [ 241 ] and mediates antigen presentation on natural-killer cells [ 242 ]. Macrophages will also infiltrate through the BBB during neuroinflammation [ 243 , 244 ], and it has been demonstrated that LPS can repress APOE gene expression in macrophages through the Tpl-2/MEK/ERK pathway [ 245 ]. Interestingly, even if the implications of adaptative immunity in AD are still largely unknown, promising small-scale studies suggest the implication of specialized CD8 T cells linked to the AD neurodegenerative process [ 246 ].…”

Glial Tiling in the Insect Nervous System

“…For the mammalian blood-brain barrier passage through tricellular junctions is detected most frequently ( Dias et al, 2021 ). In invertebrates, breaching of an intact blood-brain barrier has been described only recently in response to glial immunity induction ( Winkler et al, 2021 ). However, a preferred passage route into the nervous system is not yet known.…”

“…However, a preferred passage route into the nervous system is not yet known. Once macrophages have entered the nervous system, they move toward the neuropil, where they start to phagocytose synaptic material ( Winkler et al, 2021 ).…”

Phagocytosis Is the Sole Arm of Drosophila melanogaster Known Host Defenses That Provides Some Protection Against Microsporidia Infection

“…A recent study has documented that Drosophila pupal macrophages cross the blood-brain barrier upon receiving a PDGF-like factor, Pvf2, signal from glial cells that is induced by infection ( 90 ). Such signals have also been described for the developmental migration of hemocytes and their invasion of the embryonic epithelium ( 91 , 92 ).…”