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Mononuclear phagocyte biophysiology influences brain transendothelial and tissue migration: implication for
Induk Chung1, Marina Zelivyanskaya, Howard E Gendelman
1The Center for Neurovirology and Neurodegenerative Disorders, Departments of Pathology and Microbiology, University of Nebraska Medical Center, 985215 Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Abstract:
Mononuclear phagocyte (MP) brain migration influence neuronal damage during HIV-1-associated dementia (HAD). We demonstrate that potassium channels, expressed in human monocyte-derived macrophages (MDM), are vital for MP movement through Boyden chemotactic chambers, an artificial blood-brain barrier and organotypic hippocampal brain slices. MDM migration is inhibited by voltage-and calcium-activated potassium channel blockers that include charybodotoxin, margatoxin, agatoxin and apamin. This is observed both in uninfected and HIV-1-infected MP. The results suggest that potassium channels affect MDM brain migration through altering cell volume and shape. Such mechanisms likely affect MP-induced neuronal destruction during HAD.
Insights
Potassium channels control how mononuclear phagocytes (MP) move into the brain. Blocking these channels inhibits MP migration, potentially reducing neuronal damage in HIV-1-associated dementia (HAD).
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Mononuclear phagocytes (MP) contribute to neuronal damage in HIV-1-associated dementia (HAD).
- MP migration across the blood-brain barrier is a critical step in HAD pathogenesis.
- The role of ion channels in MP brain infiltration is not fully understood.
Purpose of the Study:
- To investigate the role of potassium channels in human monocyte-derived macrophage (MDM) brain migration.
- To determine if inhibiting potassium channels can impede MDM movement relevant to HAD.
Main Methods:
- Utilized Boyden chemotactic chambers and organotypic hippocampal brain slices to model blood-brain barrier transmigration.
- Assessed MDM migration in the presence and absence of specific potassium channel blockers (charybodotoxin, margatoxin, agatoxin, apamin).
- Examined both uninfected and HIV-1-infected MDM.
Main Results:
- Potassium channels are essential for MDM migration through artificial and biological barriers.
- Potassium channel blockers significantly inhibited MDM brain migration.
- Inhibition was observed in both uninfected and HIV-1-infected MDM.
- Potassium channels appear to regulate MDM migration by influencing cell volume and shape.
Conclusions:
- Potassium channels are critical regulators of mononuclear phagocyte migration into the brain.
- Targeting potassium channels may offer a therapeutic strategy to limit brain infiltration of MPs in HIV-1-associated dementia.
- Understanding these mechanisms can help mitigate MP-induced neuronal damage in HAD.