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Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells
Trim Lajqi1, Natascha Köstlin-Gille1, Cahit Birdir2
1Department of Neonatology, Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany.
Introduction:
Microglia are the resident immune cells of the central nervous system (CNS) that maintain tissue homeostasis and contribute to the pathogenesis of neuroinflammatory disorders. As innate immune cells, microglia can acquire memory-like states that exert long-term effects on CNS function and disease susceptibility. Increasing evidence highlights a dynamic interaction between the gut microbiota and the CNS, shaping microglial maturation and responsiveness throughout life. In addition to soluble microbial metabolites, gut-derived extracellular vesicles (EVs), including vesicles of microbial origin, have emerged as important mediators of microbiota-host communication capable of modulating brain homeostasis and inflammatory signaling; however, their role in programming microglial immune memory remains unclear.
Methods:
Here, we examined whether gut-derived small EVs influence memory-like features of primary murine microglia in vitro. Microglia were primed with small EVs followed by a secondary lipopolysaccharide (LPS) challenge, and inflammatory signaling, metabolic activity, epigenetic markers, and effector functions (migration and phagocytosis) were assessed.
Results:
Small EV priming followed by secondary LPS challenge induced a trained innate immune tolerance phenotype characterized by reduced pro-inflammatory mediator release and attenuated TLR2/4-MyD88-p38 MAPK signaling. This tolerant state was accompanied by suppressed glycolytic activity and decreased levels of activating histone H3 marks, indicating coordinated metabolic and epigenetic reprogramming. Notably, despite diminished inflammatory signaling, small EV-primed microglia displayed enhanced migratory and phagocytic capacities associated with increased ERK1/2 activation.
Discussion:
Together, these findings indicate that gut-derived small EVs can imprint memory-like programs in microglia that restrain inflammatory activation while preserving essential effector functions in vitro, suggesting a mechanism by which microbiota-brain communication may shape neuroinflammatory responses.
Insights
Gut microbes communicate with the brain via extracellular vesicles (EVs), programming microglia immune memory. These EVs restrain inflammation while maintaining microglial effector functions, influencing neuroinflammation.
Area of Science:
- Neuroimmunology
- Microbiology
- Cellular Biology
Background:
- Microglia, the CNS immune cells, can develop memory-like states impacting function and disease.
- Gut microbiota-brain communication influences microglial responses.
- Gut-derived extracellular vesicles (EVs) mediate microbiota-host communication, but their role in microglial immune memory is unknown.
Purpose of the Study:
- To investigate if gut-derived small EVs influence memory-like features in primary murine microglia.
- To assess the impact of EV priming on microglial inflammatory signaling, metabolism, epigenetics, and effector functions.
Main Methods:
- Primary murine microglia were primed with small EVs.
- A secondary lipopolysaccharide (LPS) challenge was administered.
- Assessed inflammatory mediators, signaling pathways (TLR2/4-MyD88-p38 MAPK, ERK1/2), metabolic activity, histone modifications, migration, and phagocytosis.
Main Results:
- EV priming induced trained innate immune tolerance, reducing pro-inflammatory mediators and TLR/MAPK signaling.
- This tolerance involved suppressed glycolysis and decreased activating histone H3 marks.
- EV-primed microglia showed enhanced migration and phagocytosis despite reduced inflammation, linked to ERK1/2 activation.
Conclusions:
- Gut-derived small EVs can imprint memory-like programs in microglia.
- These programs restrain inflammatory activation while preserving essential effector functions.
- This suggests a mechanism for microbiota-brain communication in shaping neuroinflammatory responses.
