Burn Injury Rewires Immune and Neuronal Extracellular Vesicle Communication.

Abstract

We examined extracellular vesicle (EV) protein alterations after burn injury to elucidate molecular pathways linking immune-neural communication and the pathophysiology of burns. Severe burn injury triggers widespread inflammation and metabolic stress with downstream consequences. EVs are essential mediators of cell-to-cell communication and protein transport for regulating inflammation, metabolism, and neuronal signaling that may reflect burn-related alterations. Plasma EVs from 37 adult burn patients (≥15% total body surface area burn [TBSA]) and 21 nonburn controls were analyzed. An age-restricted subcohort (<40 years) was additionally evaluated to minimize potential confounding of age. A subset (4 per group) underwent cell type-specific EV enrichment. Proteomic profiling and functional enrichment analyses, including gene ontology (GO) over-representation analysis (ORA), Reactome gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA), were performed to identify differential protein abundance and associated biological pathways. Burn injury produced distinct alterations in EV proteomic profiles. Among 919 detected proteins, 326 were decreased and 593 were increased. The 5 most significant proteins (adjusted P -value<0.05) distinguishing burns from controls were CRP, ITGA11, MYH9, CALR, and ANTXR2. GO ORA, Reactome GSEA, and IPA consistently identified enrichment of immune activation and inflammatory regulation pathways, including immune cell chemotaxis, acute-phase signaling, cytokine signaling, complement activation, coagulation, and cellular stress pathways. Similar inflammatory pathway enrichment persisted in the age-restricted subcohort. Exploratory analyses of cell type-enriched EVs demonstrated distinct proteomic trends across immune and neuronal EV populations, although no subtype-specific proteins exhibited statistical significance. Burn injury profoundly alters EV cargo across general, immune, and neuronal types, reflecting proinflammatory and neuroimmune-associated signaling. This coordinated EV remodeling may reflect the hyperinflammatory responses, altered healing, and downstream biological pathway alterations. EV-based biomarkers may enable improved diagnostic and therapeutic strategies to mitigate dysregulated immune and healing responses in burn patients.