Defining blood-induced microglia functions in neurodegeneration through multiomic profiling
Andrew S Mendiola1,2, Zhaoqi Yan1,2, Karuna Dixit1,2
1Gladstone Institutes, San Francisco, CA, USA.
Nature Immunology
|June 8, 2023
Summary
Blood proteins crossing the blood-brain barrier activate microglia, driving neurodegeneration. Targeting fibrinogen significantly reduces these harmful effects, offering new therapeutic avenues for neurological diseases.
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.
