Blocking neuroinflammation at the blood-brain barrier
Demyelinating chronic inflammatory conditions such as multiple sclerosis are associated with entry of leukocytes into the CNS vasculature through the blood-brain barrier. Calvier et al. used a mouse model of experimental autoimmune encephalomyelitis (EAE) to investigate the impact of loss-of-function mutations in the apolipoprotein E receptor 2 (ApoER2) on monocyte interactions with vascular endothelial cells and induction of EAE after immunization with a myelin glycoprotein peptide. Mice lacking ApoER2 or with mutations in the ApoER2 cytoplasmic domain impairing signaling exhibited decreased monocyte adherence to vascular endothelium during flow and developed milder clinical symptoms in the EAE model. These findings suggest that inhibition of ApoER2 may provide a therapeutic approach to neuroinflammatory diseases that does not also lead to generalized immunosuppression.
Abstract
Under normal conditions, the blood-brain barrier effectively regulates the passage of immune cells into the central nervous system (CNS). However, under pathological conditions such as multiple sclerosis (MS), leukocytes, especially monocytes, infiltrate the CNS where they promote inflammatory demyelination, resulting in paralysis. Therapies targeting the immune cells directly and preventing leukocyte infiltration exist for MS but may compromise the immune system. Here, we explore how apolipoprotein E receptor 2 (ApoER2) regulates vascular adhesion and infiltration of monocytes during inflammation. We induced experimental autoimmune encephalitis in ApoER2 knockout mice and in mice carrying a loss-of-function mutation in the ApoER2 cytoplasmic domain. In both models, paralysis and neuroinflammation were largely abolished as a result of greatly diminished monocyte adherence due to reduced expression of adhesion molecules on the endothelial surface. Our findings expand our mechanistic understanding of the vascular barrier, the regulation of inflammation and vascular permeability, and the therapeutic potential of ApoER2-targeted therapies.
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