Plasma extracellular vesicles released after severe burn injury modulate macrophage phenotype and function

Area of Science:

• Immunology
• Cell Biology
• Trauma Research

Background:

• Severe burn injury triggers significant immune dysfunction, leading to high mortality rates from infections and organ failure.
• Burn injury induces a biphasic immune response: an initial hyper-inflammatory phase followed by a later immunosuppressive phase.
• Damage-associated molecular pattern molecules like high-mobility group protein 1 (HMGB1) and cytokines such as IL-1β are implicated in burn-induced immune responses.

Purpose of the Study:

• To investigate the role of extracellular vesicles (EVs) isolated from burn injury models in modulating immune responses.
• To determine the in vivo and in vitro effects of burn-derived EVs on immune cell phenotype and function.
• To assess the cargo of burn-derived EVs and their correlation with immune dysfunction.

Main Methods:

• Isolation of EVs from mice subjected to severe burn injury.
• Adoptive transfer of burn-derived EVs into naïve mice and RAW264.7 macrophages.
• Analysis of cytokine profiles, immune gene expression, and cellular responses post-EV transfer.
• Quantification of high-mobility group protein 1 (HMGB1) cargo within burn EVs.

Main Results:

• EVs from early burn injury (burn EVs) induced hallmark cytokine responses in naïve mice.
• Transfer of burn EVs to macrophages replicated functional and gene expression changes associated with post-burn immune dysfunction.
• Early burn EVs (24h) promoted pro-inflammatory cytokine secretion (MCP-1, IL-12p70, IFNγ), while later EVs (1-2+ wk) suppressed responses to LPS.
• Increased HMGB1 cargo was observed in burn EVs from days 1 to 7 post-injury.

Conclusions:

• Burn-derived EVs play a critical role in mediating immune outcomes following severe burn injury.
• These EVs can transfer immune-modulatory signals, recapitulating the biphasic immune dysfunction observed after burns.
• Burn EVs, particularly those enriched with HMGB1, are key contributors to post-burn immune dysregulation and increased infection susceptibility.