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Updated: Jun 9, 2026
Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
Extracellular Vesicle-Associated IL4 Displays Enhanced Anti-Inflammatory Properties in Microglial Cells
Giulia Marostica1, Chiara Frigè1, Annamaria Finardi1
1Institute of Experimental Neurology, Division of Neuroscience IRCCS Ospedale San Raffaele Milan Italy.
Abstract:
Neuroinflammation and neurodegeneration are strictly related phenomena, characterized by dysregulation of microglia, central nervous system (CNS) resident immune cells. Interleukin-4 (IL4) has shown beneficial abilities to re-establish microglial homeostasis in experimental models of CNS traumatic injury, stroke and multiple sclerosis, but its optimal administration system remains uncertain. Here, we show that extracellular vesicles (EVs) released by engineered murine microglia BV2 cells constitutively expressing IL4 induced a faster and enhanced anti-inflammatory phenotype in wild type BV2 cells (as assessed by IL4R downstream signalling), compared with soluble IL4. This effect was blunted by an anti-IL4 antibody, while it was not dampened by knocking out the IL4 receptor α subunit in EV-releasing BV2 cells, suggesting that IL4 was localized on the EV surface and did not necessitate to be co-conveyed with the receptor to exert its function. BV2 cells treated with EV-associated IL4, compared with soluble IL4, demonstrated delayed permanence of IL4R in the early endosome, suggesting amplified signalling effects. In conclusion, we here show that the association of IL4 with microglia-derived EVs improve its anti-inflammatory effect in an in vitro murine microglial model, which may inform on novel therapeutic opportunities to restore microglia in human disorders marked by neuroinflammation.
Insights
Extracellular vesicles (EVs) carrying Interleukin-4 (IL4) enhance microglial anti-inflammatory effects more than soluble IL4. This suggests EVs may offer novel therapeutic strategies for neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuroinflammation and neurodegeneration are linked to microglial dysfunction in the central nervous system (CNS).
- Interleukin-4 (IL4) shows promise in restoring microglial homeostasis in CNS injury models, but optimal delivery is unclear.
Purpose of the Study:
- To investigate if extracellular vesicles (EVs) expressing IL4 can improve the anti-inflammatory effects of IL4 on microglia.
- To compare the efficacy of IL4 delivered via EVs versus soluble IL4 in a murine microglial model.
Main Methods:
- Engineered murine microglia (BV2 cells) constitutively expressing IL4 were used to generate IL4-carrying EVs.
- Wild-type BV2 cells were treated with IL4-EVs or soluble IL4 to assess anti-inflammatory responses via IL4R signaling.
- Experiments included blocking IL4 with antibodies and knocking out the IL4 receptor alpha subunit to elucidate the mechanism of action.
Main Results:
- IL4-EVs induced a faster and enhanced anti-inflammatory phenotype in BV2 cells compared to soluble IL4.
- The effect of IL4-EVs was IL4-dependent but did not require co-delivery of the IL4 receptor.
- IL4-EVs led to prolonged IL4 receptor permanence in early endosomes, suggesting amplified signaling.
Conclusions:
- IL4 associated with microglia-derived EVs enhances its anti-inflammatory efficacy in an in vitro murine microglial model.
- This finding suggests a potential novel therapeutic strategy using IL4-loaded EVs to restore microglial function in neuroinflammatory human disorders.
