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

Abstract

Extracellular vesicles (EVs) have emerged as key regulators of immune function across multiple diseases. Severe burn injury is a devastating trauma with significant immune dysfunction that results in an ∼12% mortality rate due to sepsis‐induced organ failure, pneumonia, and other infections. Severe burn causes a biphasic immune response: an early (0–72 h) hyper‐inflammatory state, with release of damage‐associated molecular pattern molecules, such as high‐mobility group protein 1 (HMGB1), and proinflammatory cytokines (e.g., IL‐1β), followed by an immunosuppressive state (1–2+ wk post injury), associated with increased susceptibility to life‐threatening infections. We have reported that early after severe burn injury HMGB1 and IL‐1β are enriched in plasma EVs. Here we tested the impact of EVs isolated after burn injury on phenotypic and functional consequences in vivo and in vitro using adoptive transfers of EV. EVs isolated early from mice that underwent a 20% total body surface area burn injury (burn EVs) caused similar hallmark cytokine responses in naïve mice to those seen in burned mice. Burn EVs transferred to RAW264.7 macrophages caused similar functional (i.e., cytokine secretion) and immune gene expression changes seen with their associated phase of post‐burn immune dysfunction. Burn EVs isolated early (24 h) induced MCP‐1, IL‐12p70, and IFNγ, whereas EVs isolated later blunted RAW proinflammatory responses to bacterial endotoxin (LPS). We also describe significantly increased HMGB1 cargo in burn EVs purified days 1 to 7 after injury. Thus, burn EVs cause immune outcomes in naïve mice and macrophages similar to findings after severe burn injury, suggesting EVs promote post‐burn immune dysfunction.

Clinical Characteristics of Bloodstream Infection in Immunosuppressed Patients: A 5-Year Retrospective Cohort Study

“…Immunosuppressive (IS) status refers to low immune response. Generally, typical immunosuppressive status includes patients with hematological diseases, tumor, oral immunosuppressive medications, solid-organ transplant, stem cell transplant, or bone marrow transplant, and atypical immunosuppressive status includes patients with diabetes mellitus, liver cirrhosis, and burns ( Mylotte and Tayara, 2000 ; Li et al., 2021 ; Willis et al., 2021 ). Studies revealed that immunosuppression could result from critical surgery as well ( Si et al., 2021 ), and sometimes postoperative patients are susceptible to infections caused by opportunistic pathogens ( Mada et al., 2020 ; Shipman et al., 2021 ).…”

Predictive value of perioperative monocyte counts for bacteremia and 90-day all-cause mortality in patients with severe burn

“…Monocytes, which are the precursors to macrophages and dendritic cells, are the main effector cells against invading bacteria. Accumulating evidence suggests that decreased monocytes, which are very common in burns, sepsis and following major surgeries, may be intimately associated with patient outcomes [23,24]. For example, Osuka et al noted that monocyte count at day 10 was predictive of 30-day mortality in patients with extensive burns [4].…”

Characterization of the Basal and mTOR-Dependent Acute Pulmonary and Systemic Immune Response in a Murine Model of Combined Burn and Inhalation Injury

“…All data were examined in GraphPad Prism Version 9.0 for Windows and analyzed using a one-way analysis of variance (ANOVA) with a Tukey post-test. For NanoString, a negative binomial mixture model, simplified negative binomial model, or loglinear model was used depending on each gene’s mean expression compared to the background threshold, as we described previously [ 71 , 72 ]. Multiple testing correction was performed using the method of Benjamini–Yekutieli.…”