Burn Injury Induces Proinflammatory Plasma Extracellular Vesicles That Associate with Length of Hospital Stay in Women: CRP and SAA1 as Potential Prognostic Indicators

Severe burn injury is a devastating form of trauma that results in persistent immune dysfunction with associated morbidity and mortality. The underlying drivers of this immune dysfunction remain elusive, and there are no prognostic markers to identify at-risk patients. Extracellular vesicles (EVs) are emerging as drivers of immune dysfunction as well as biomarkers. We investigated if EVs after burn injury promote macrophage activation and assessed if EV contents can predict length of hospital stay. EVs isolated early from mice that received a 20% total body surface area (TBSA) burn promoted proinflammatory responses in cultured splenic macrophages. Unbiased LC-MS/MS proteomic analysis of early EVs (<72 h post-injury) from mice and humans showed some similarities including enrichment of acute phase response proteins such as CRP and SAA1. Semi-unbiased assessment of early human burn patient EVs found alterations consistent with increased proinflammatory signaling and loss of inhibition of CRP expression. In a sample of 50 patients with large burn injury, EV SAA1 and CRP were correlated with TBSA injury in both sexes and were correlated with length of hospital stay in women. These findings suggest that EVs are drivers of immune responses after burn injury and their content may predict hospital course.

[1]  B. Cairns,et al.  Plasma extracellular vesicles released after severe burn injury modulate macrophage phenotype and function , 2021, Journal of leukocyte biology.

[2]  A. Lagares,et al.  Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients , 2021, Biomedicines.

[3]  T. Afonyushkin,et al.  Extracellular vesicles are associated with C-reactive protein in sepsis , 2021, Scientific Reports.

[4]  J. Hou,et al.  Coupled liquid biopsy and bioinformatics for pancreatic cancer early detection and precision prognostication , 2021, Molecular Cancer.

[5]  F. Crews,et al.  Extracellular microvesicles promote microglia‐mediated pro‐inflammatory responses to ethanol , 2021, Journal of neuroscience research.

[6]  J. Köhl,et al.  Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients , 2020, Frontiers in Immunology.

[7]  J. Travers,et al.  Thermal Burn Injury Generates Bioactive Microvesicles: Evidence for a Novel Transport Mechanism for the Lipid Mediator Platelet-Activating Factor (PAF) That Involves Subcellular Particles and the PAF Receptor , 2020, The Journal of Immunology.

[8]  Timothy M. D. Ebbels,et al.  Predictive modelling using pathway scores: robustness and significance of pathway collections , 2019, BMC Bioinformatics.

[9]  B. Cairns,et al.  One-hit wonder: Late after burn injury, granulocytes can clear one bacterial infection but cannot control a subsequent infection. , 2019, Burns : journal of the International Society for Burn Injuries.

[10]  Dylan T Burnette,et al.  Reassessment of Exosome Composition , 2019, Cell.

[11]  C. Théry,et al.  Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication , 2019, Nature Cell Biology.

[12]  ειδικούς στόχους,et al.  (2016) , 2018 .

[13]  Laura E. Herring,et al.  Chronic E‐Cigarette Exposure Alters the Human Bronchial Epithelial Proteome , 2018, American journal of respiratory and critical care medicine.

[14]  S. Drechsler,et al.  Extracellular Vesicles as Markers and Mediators in Sepsis , 2018, Theranostics.

[15]  Wesley H. Stepp,et al.  Research in Acute Lung Injury and Pulmonary Fibrosis Blocking CXCL1-dependent neutrophil recruitment prevents immune damage and reduces pulmonary bacterial infection after inhalation injury , 2022 .

[16]  B. Cairns,et al.  Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury , 2018, Journal of leukocyte biology.

[17]  B. Cairns,et al.  HMGB1/IL-1β complexes in plasma microvesicles modulate immune responses to burn injury , 2018, PloS one.

[18]  Graça Raposo,et al.  Shedding light on the cell biology of extracellular vesicles , 2018, Nature Reviews Molecular Cell Biology.

[19]  Stephen J. Capuzzi,et al.  Design and Profiling of a Subcellular Targeted Optogenetic cAMP-Dependent Protein Kinase. , 2017, Cell chemical biology.

[20]  Wesley H. Stepp,et al.  Differential regulation of innate immune cytokine production through pharmacological activation of Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) in burn patient immune cells and monocytes , 2017, PloS one.

[21]  Laura E. Herring,et al.  Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis , 2017, PLoS genetics.

[22]  Michael J. Emanuele,et al.  The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome , 2017, The Journal of Biological Chemistry.

[23]  F. Crews,et al.  Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7 , 2017, Journal of Neuroinflammation.

[24]  J. Handy,et al.  Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity , 2016, PloS one.

[25]  Bruce A Cairns,et al.  Timeline of health care-associated infections and pathogens after burn injuries. , 2016, American journal of infection control.

[26]  B. Cairns,et al.  Direct detection of blood nitric oxide reveals a burn-dependent decrease of nitric oxide in response to Pseudomonas aeruginosa infection. , 2016, Burns : journal of the International Society for Burn Injuries.

[27]  Dong Hun Lee,et al.  Serum amyloid A1 is induced by UV irradiation and detected by toll-like receptor 4 to causes skin inflammation. , 2016, Journal of dermatological science.

[28]  James W. Clancy,et al.  Biology and biogenesis of shed microvesicles , 2016, Small GTPases.

[29]  M. Maltenfort,et al.  National Trends in Burn and Inhalation Injury in Burn Patients: Results of Analysis of the Nationwide Inpatient Sample Database , 2015, Journal of burn care & research : official publication of the American Burn Association.

[30]  Hsu Ma,et al.  The impact of inhalation injury in patients with small and moderate burns. , 2014, Burns : journal of the International Society for Burn Injuries.

[31]  B. Cairns,et al.  Flagellin Treatment Prevents Increased Susceptibility to Systemic Bacterial Infection after Injury by Inhibiting Anti-Inflammatory IL-10+ IL-12- Neutrophil Polarization , 2014, PloS one.

[32]  Haibo Zhou,et al.  Bronchoscopy-Derived Correlates of Lung Injury following Inhalational Injuries: A Prospective Observational Study , 2013, PloS one.

[33]  Sheng Liu,et al.  High-Mobility Group Box-1 Induces Proinflammatory Cytokines Production of Kupffer Cells through TLRs-Dependent Signaling Pathway after Burn Injury , 2012, PloS one.

[34]  M. Krzyżaniak,et al.  Vagal Nerve Stimulation Blocks Peritoneal Macrophage Inflammatory Responsiveness After Severe Burn Injury , 2012, Shock.

[35]  S. Blot,et al.  Burns, inhalation injury and ventilator-associated pneumonia: value of routine surveillance cultures. , 2012, Burns : journal of the International Society for Burn Injuries.

[36]  C. Heng,et al.  Effect of serum amyloid A1 treatment on global gene expression in THP-1-derived macrophages , 2012, Inflammation Research.

[37]  D. Herndon,et al.  Long-Term Persistance of the Pathophysiologic Response to Severe Burn Injury , 2011, PloS one.

[38]  Meghana Kulkarni.  Digital multiplexed gene expression analysis using the NanoString nCounter system. , 2011, Current protocols in molecular biology.

[39]  S. Wolf,et al.  An historical perspective on advances in burn care over the past 100 years. , 2009, Clinics in plastic surgery.

[40]  M. Peck,et al.  A global plan for burn prevention and care. , 2009, Bulletin of the World Health Organization.

[41]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[42]  D. Herndon,et al.  CHARACTERIZATION OF THE INFLAMMATORY RESPONSE DURING ACUTE AND POST-ACUTE PHASES AFTER SEVERE BURN , 2008, Shock.

[43]  J. Jeng,et al.  National Burn Repository 2007 Report: A Synopsis of the 2007 Call for Data , 2008, Journal of burn care & research : official publication of the American Burn Association.

[44]  R. Gamelli,et al.  Temporal Cytokine Profiles in Severely Burned Patients: A Comparison of Adults and Children , 2008, Molecular medicine.

[45]  B. Cairns,et al.  Toll-like receptor 2 and 4 ligation results in complex altered cytokine profiles early and late after burn injury. , 2008, The Journal of trauma.

[46]  B. Cairns,et al.  Downregulation of Immune Signaling Genes in Patients With Large Surface Burn Injury , 2007, Journal of burn care & research : official publication of the American Burn Association.

[47]  Vijay A. Singh,et al.  The Effects of Preexisting Medical Comorbidities on Mortality and Length of Hospital Stay in Acute Burn Injury: Evidence From a National Sample of 31,338 Adult Patients , 2007, Annals of surgery.

[48]  L. Marnell,et al.  C-reactive protein: ligands, receptors and role in inflammation. , 2005, Clinical immunology.

[49]  B. Cairns,et al.  Increased Toll-like receptor 4 expression on T cells may be a mechanism for enhanced T cell response late after burn injury. , 2005, The Journal of trauma.

[50]  R. Sheridan,et al.  What's new in burns and metabolism. , 2004, Journal of the American College of Surgeons.

[51]  K. Tracey,et al.  Reversing established sepsis with antagonists of endogenous high-mobility group box 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  E. Kovacs,et al.  THE ROLE OF INTERLEUKIN 6 IN INTERFERON-γ PRODUCTION IN THERMALLY INJURED MICE , 2000 .

[53]  S. Wood,et al.  The physiological structure of human C-reactive protein and its complex with phosphocholine. , 1999, Structure.

[54]  J. Volanakis.  COMPLEMENT ACTIVATION BY C‐REACTIVE PROTEIN COMPLEXES * , 1982, Annals of the New York Academy of Sciences.

[55]  Haibo Zhou,et al.  Biomarkers in Lung Diseases : from Pathogenesis to Prediction to New Therapies Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury , 2015 .

[56]  E. Kovacs,et al.  Sex differences and estrogen modulation of the cellular immune response after injury. , 2008, Cellular immunology.

[57]  E. Kovacs,et al.  The role of interleukin 6 in interferon-gamma production in thermally injured mice. , 2000, Cytokine.