FLT-3 expression and function on microglia in multiple sclerosis
Cynthia A DeBoy1, Horea Rus, Cosmin Tegla
1Neurology, Johns Hopkins University, Pathology 627, 600 N. Wolfe Street, Baltimore, MD 21287,USA.
Abstract:
Inflammatory cell infiltration and resident microglial activation within the central nervous system (CNS) are pathological events in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). While MS therapies target the peripheral immune system, no treatment is currently known to also modulate microglia. FMS-like tyrosine-3 (FLT-3) is expressed on hematopoietic and dendritic cells. We reported that FLT-3 inhibition ameliorates early actively induced EAE by predominantly modulating dendritic cell function as compared to microglia. We demonstrate in this report that FLT-3 is expressed in perivascular cuffs, brain parenchyma and in non-lesioned gray and white matter within MS brain but not in these regions within control brain. Furthermore, we demonstrate that FLT-3 is expressed on two populations of cells within MS brain; one which expresses the dendritic cell marker CD209, and the other which does not, suggesting that FLT-3 within MS brain is expressed on infiltrating dendritic cells and a non-dendritic cell such as microglia. Additionally, we report that FLT-3 inhibition in murine microglia blocks, in a dose-dependent manner, IFN-γ-induced expression of MHC class II and CD86, and LPS-induced secretion of IL-6. These data suggest that FLT-3 is involved in microglial cells' capacity to respond to environmental cues to function as antigen presenting cells and mediate CNS inflammation. Furthermore these data suggest that FLT-3 may be a therapeutic target on microglia to mitigate CNS inflammation.
Insights
FMS-like tyrosine-3 (FLT-3) is present in multiple sclerosis (MS) brain cells, including microglia. Inhibiting FLT-3 in mice reduced inflammation and may offer a new therapeutic target for MS.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Microglial activation and inflammatory cell infiltration are key pathological features of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
- Current MS therapies primarily target the peripheral immune system, leaving microglia, the resident immune cells of the central nervous system (CNS), untargeted.
- FMS-like tyrosine-3 (FLT-3) is known to be expressed on hematopoietic and dendritic cells, and its inhibition was previously shown to ameliorate EAE by modulating dendritic cell function.
Purpose of the Study:
- To investigate the expression and role of FLT-3 in the CNS, particularly in the context of MS.
- To determine if FLT-3 is expressed on microglia within the MS brain and if it influences microglial function.
- To explore the potential of FLT-3 as a therapeutic target for mitigating CNS inflammation in MS.
Main Methods:
- Immunohistochemical analysis of FLT-3 expression in MS brain tissue compared to control brain.
- Characterization of FLT-3 expressing cells in MS brain using markers like CD209 (dendritic cell marker).
- In vitro studies involving inhibition of FLT-3 in murine microglia to assess its impact on inflammatory responses (MHC class II, CD86 expression, IL-6 secretion).
Main Results:
- FLT-3 expression was detected in perivascular cuffs, brain parenchyma, and non-lesioned areas of MS brains, but not in control brains.
- FLT-3 was found on two cell populations in MS brain: CD209-positive (dendritic cells) and CD209-negative cells (potentially microglia).
- FLT-3 inhibition in murine microglia dose-dependently blocked IFN-γ-induced MHC class II and CD86 expression and LPS-induced IL-6 secretion.
Conclusions:
- FLT-3 is expressed in the MS brain on both infiltrating dendritic cells and resident microglia.
- FLT-3 plays a role in microglial activation and their function as antigen-presenting cells, contributing to CNS inflammation.
- FLT-3 inhibition presents a potential therapeutic strategy for modulating microglial activity and mitigating neuroinflammation in MS.
