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Burn Injury Rewires Immune and Neuronal Extracellular Vesicle Communication
*Kristin Grimsrud1, *Tajia Green
3, *David Wang
2, *Aijun Wang
2, Tina Palmieri
21Pathology, University of California, Davis, Sacramento, California; 2Surgery, University of California, Davis, Sacramento, California; 3Shriners Children's Hospital Northern California, Sacramento, California
Objective: Severe burn injury triggers widespread inflammation and metabolic stress that generates downstream consequences. Extracellular vesicles (EVs) are essential mediators of cell-to-cell communication, transporting proteins that regulate inflammation, metabolism, and neuronal signaling that may reflect burn inflammation. Our specific aim was to examine EV protein cargo alterations after burn injury and elucidate molecular pathways linking immune-neural communication and the pathophysiology of burn healing.
Methods: Remnant plasma samples from 37 hospitalized burn patients with greater than 15% total body surface area burn were compared to 21 nonburn patients without severe comorbidities (control). EVs were isolated from patient plasma, and a subset (4 burns, 4 controls) was further sub-isolated to enrich for EVs from four tissue/cell populations. Proteomic profiling was employed to identify differential protein expression between burn patients and non-burn controls. Bioinformatic analysis using Ingenuity Pathway Analysis mapped proteins to functional biological pathways.
Results: Burn injury produced distinct, cell type-specific EV signatures. Among 914 proteins passing quality control, 322 were downregulated and 592 were upregulated. The most affected pathways fell within the immune system activation and the inflammatory response regulation network, including immune cell chemotaxis and movement, acute phase response signaling, cytokine cascade in inflammation, regulation of cell adhesion and polarization, and complement system activation. The five most statistically significant (p
<0.045) proteins distinguishing burn patients from controls were CRP, ITGA11, MYH9, CALR, and ANTXR2. Sub-isolated EVs revealed cell type-specific pathway perturbations: macrophage-derived EVs showed prominent changes in lipid synthesis, cellular proliferation, epithelial development, and neovascularization, while neutrophil-derived EVs demonstrated alterations in immunomodulation and cellular dynamics. Neuron-derived EVs had interconnected regulation of cellular transformation and immune modulation, whereas microglial EVs exhibited alterations related to tumorigenesis, necrosis pathways, septic shock, and cell death regulation.
Conclusions: Burn injury profoundly reprograms EV cargo across immune and neuronal cell types, promoting pro-inflammatory and neuro-sensitizing signaling. This coordinated EV shift likely contributes to the hyperinflammatory response, alterations in wound healing, upregulation of tumorigenic pathways and alterations in other downstream pathways. EV-based biomarkers and signaling pathways identified here may support improved diagnostic and therapeutic strategies to mitigate dysregulated immune and healing responses in burn patients.
Figure 1. Proteomic profile network associations from macrophage (1.A), neutrophil (1.B), microglia (1.C) and neuron (1.D) derived extracellular vesicles.
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