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Impaired signaling of Transcription factors NF-ƘB and NRF2 in CX3CR1-deficient microglia leads to altered neuroinflammation and phagocytosis: implications in tauopathies
|Authors:||Castro-Sánchez, Sara; García-Yagüe, Ángel Juan; Galán-Ganga, Marcos; López-Royo, Teresa; Kügler, Sebastian; Lastres-Becker, Isabel|
|Citation:||5th Symposium on Biomedical Research (2018)|
|Abstract:||[Introduction]: TAU protein aggregation is the main characteristic of a group of age-related neurodegenerative diseases called tauopathies. One of the key hallmarks associated with neurodegeneration is the presence of low-grade chronic inflammation, indicating a crosstalk between damaged neuron and glial cells. Previously we have shown that TAUP301L overexpressing neurons
released CX3CL1 that activates anti-inflammatory NRF2 signalling in microglial cells in vitro and in vivo. However, the potential role of CX3CR1 in the context of TAU pathology and its implication neuroinflammation are poorly described.|
[Material and Methods]: Pro-inflammatory markers in immortalized microglia cells (IMG) treated with CX3CL1 were analysed. We also studied mRNA expression levels of NF-ƘB, anti-inflammatory Nrf2 signalling and TAM receptors (TYRO3, AXL and MER) in CX3CR1-deficient primary microglia cells. Finally, the effect of sulforaphane (SFN), a NRF2 inducer, was examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with SFN (50mg/kg, i.p) during three weeks.
[Results]: In this study we show that CX3CL1 treatment induced NF-ƘB-p65 and pro-inflammatory cytokines expression. On the other hand, CX3CR1-deficient primary microglia cells present impaired NF-ƘB mRNA expression levels and decreased anti-inflammatory NRF2 signalling, suggesting a dual role of CX3CL1/CX3CR1 axis in neuroinflammation. Lack of CX3CR1 microglia exhibit decreased mRNA expression levels of TAM receptors (TYRO3, AXL and MER) that functionally results in a deficiency in phagocytosis. SFN treatment reverses astrogliosis in Cx3cr1+/+ and Cx3cr1-/-, whereas at microglial level we did not see any improvement in the Cx3cr1-/- mice.
[Conclusions]: These findings suggest that CX3CR1-NRF2 axis activation is essential in the modulation of microglial activation associated with tauopathy, and that the associated polymorphisms of CX3CR1 must be taken into account in the design of pharmacological strategies for the treatment of taupathies.
|Description:||Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.|
|Appears in Collections:||(IIBM) Comunicaciones congresos|