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Area of Science:

  • Neuroimmunology
  • Molecular Neurology
  • Proteomics

Background:

  • Blood-brain barrier disruption and subsequent protein extravasation are critical in neurological disorders.
  • Innate immune cell activation, particularly microglia, is a key feature and therapeutic target in neuroinflammation.
  • The precise mechanisms by which blood proteins influence innate immune cell polarization remain poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms of blood protein-induced innate immune cell polarization.
  • To define the role of specific blood proteins, like fibrinogen, in microglia-mediated neurotoxicity.
  • To identify potential therapeutic targets for modulating neuroinflammation driven by blood-brain barrier dysfunction.

Main Methods:

  • Development of an unbiased multiomic and genetic loss-of-function pipeline.
  • Transcriptomic and global phosphoproteomic analysis of blood-induced microglia and macrophage polarization.
  • Genetic manipulation in mouse models of Alzheimer's disease and multiple sclerosis.

Main Results:

  • Blood exposure induced significant microglial transcriptional alterations, including genes related to oxidative stress and neurodegeneration.
  • Comparative multiomics revealed distinct receptor-mediated transcriptional programs in microglia and macrophages triggered by blood proteins.
  • Fibrinogen deletion substantially reversed blood-induced neurodegenerative gene signatures in microglia.
  • Eliminating the fibrinogen-binding motif on CD11b reduced shared neurodegenerative and lipid metabolism signatures in Alzheimer's and multiple sclerosis models.

Conclusions:

  • Blood proteins, particularly fibrinogen, play a crucial role in polarizing microglia towards a neurotoxic state.
  • Targeting fibrinogen interactions with microglia presents a promising strategy for treating neurodegenerative and neuroinflammatory conditions.
  • The study provides a valuable resource for understanding blood-innate immunity interactions in neurological diseases.