Dual microglia effects on blood brain barrier permeability induced by systemic inflammation
Koichiro Haruwaka1,2,3, Ako Ikegami1, Yoshihisa Tachibana1
1Division of System Neuroscience, Kobe University Graduate School of Medicine, Kobe, Japan.
Abstract:
Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.
Insights
Systemic inflammation causes brain microglia to migrate to blood vessels, initially protecting the blood-brain barrier (BBB). However, prolonged inflammation leads to microglia impairing BBB function, impacting neural health.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are the resident immune cells of the brain, surveying the parenchyma and responding to various stimuli.
- The role of microglia in systemic disease and their interaction with the blood-brain barrier (BBB) integrity is not fully understood.
- Systemic inflammation can affect brain function, but the mechanisms involving microglia and the BBB require further investigation.
Purpose of the Study:
- To investigate the role of microglia in response to systemic inflammation and their impact on blood-brain barrier (BBB) integrity.
- To elucidate the cellular and molecular mechanisms by which microglia interact with the cerebral vasculature during systemic immune activation.
Main Methods:
- Simultaneous in vivo imaging was employed to observe microglial behavior and BBB integrity in real-time.
- Investigated the involvement of CCR5 signaling in microglial migration.
- Assessed the expression of tight-junction proteins, such as Claudin-5, and microglial interactions with endothelial cells and astrocytes.
Main Results:
- Systemic inflammation triggers CCR5-dependent migration of brain-resident microglia towards the cerebral vasculature.
- Vessel-associated microglia initially support BBB integrity by expressing Claudin-5 and interacting with endothelial cells.
- Sustained inflammation results in microglia phagocytosing astrocytic end-feet, leading to impaired BBB function.
Conclusions:
- Microglia exhibit a dual role in maintaining BBB integrity, acting as both protectors and disruptors depending on the inflammatory context.
- Microglial interactions with the BBB are crucial for understanding how systemic immune activation influences neural functions and brain homeostasis.
- These findings have implications for neurological disorders associated with systemic inflammation and compromised BBB function.
