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Extracellular Histones Associate with Blood-Brain Barrier Disruption and Astrocyte-Mediated Neuroinflammation During
Fatemeh Fattahi1,2, Jamison J Grailer2, Elizabeth A Malan2
1Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Extracellular histones released during sepsis contribute to brain dysfunction by damaging the blood-brain barrier and activating glial cells. Targeting these histones may offer a new treatment for sepsis-associated encephalopathy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Histones are released into circulation during sepsis, potentially impacting neurological function.
- Sepsis-associated encephalopathy (SAE) involves brain dysfunction, and extracellular histones may exacerbate it.
Purpose of the Study:
- To investigate the role of extracellular histones in sepsis-induced brain injury, blood-brain barrier (BBB) disruption, and neuroinflammation.
Main Methods:
- Utilized a cecal ligation and puncture (CLP) sepsis model in mice.
- Assessed histone levels, BBB permeability (FITC-inulin, Texas Red-dextran), complement activation, and glial cell responses (GFAP, Iba1).
- Conducted in vitro experiments with astrocytes to examine histone uptake, calcium signaling, cytokine release, and NLRP3 inflammasome activation.
Main Results:
- Histone accumulation and increased soluble histones were observed in the brain post-CLP.
- BBB permeability was significantly increased following CLP.
- Activated astrocytes and microglia, along with complement activation, were detected in the brain.
- Astrocytes released and took up histones, with histone exposure leading to calcium influx, cytokine secretion, and NLRP3 inflammasome activation.
Conclusions:
- Extracellular histones contribute to neuroinflammation, BBB disruption, and glial activation during sepsis.
- Histones may play a critical role in the pathogenesis of SAE.
- Extracellular histones represent a potential therapeutic target for sepsis-related neurological complications.
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