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Analysis of Lymphocyte Extravasation Using an In Vitro Model of the Human Blood-brain Barrier
Published on: April 5, 2017
GM-CSF promotes migration of human monocytes across the blood brain barrier
Daphne Y S Vogel1,2, Gijs Kooij1, Priscilla D A M Heijnen1
1Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands.
Abstract:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte-macrophages colony-stimulating factor (GM-CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood-brain barrier. This study describes the effect of GM-CSF on human monocytes, macrophages, and microglia. Furthermore, the expression of GM-CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM-CSF enhances monocyte migration across human blood-brain barrier endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM-CSF is highly expressed by microglia and macrophages in MS lesions. The GM-CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM-CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM-CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) drives monocyte migration into the central nervous system (CNS) and is abundant in multiple sclerosis (MS) lesions, activating immune cells.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS).
- Monocyte infiltration into the CNS is critical for MS pathogenesis.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in myeloid cell migration across the blood-brain barrier.
Purpose of the Study:
- To investigate the effect of GM-CSF on human monocytes, macrophages, and microglia.
- To examine GM-CSF and its receptor expression in the human CNS in health and MS.
- To elucidate the role of GM-CSF in monocyte migration and immune cell activation in MS.
Main Methods:
- In vitro assessment of monocyte migration across human blood-brain barrier endothelial cells.
- Immunohistochemical analysis of human brain tissues from MS patients and controls.
- Phenotypic analysis of human macrophages treated with GM-CSF.
Main Results:
- GM-CSF significantly enhanced human monocyte migration across the blood-brain barrier in vitro.
- GM-CSF was highly expressed by microglia and macrophages within MS lesions.
- The GM-CSF receptor was detected on neurons and astrocytes in MS lesions.
- GM-CSF induced an intermediate activation status in human macrophages, resembling phenotypes in active MS lesions.
Conclusions:
- GM-CSF is a potent stimulator of monocyte migration into the CNS.
- GM-CSF is significantly present in the inflamed CNS during MS.
- GM-CSF likely contributes to MS pathogenesis by activating macrophages and microglia within the CNS.
