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Multiplexed Human Gene Expression Analysis Reveals a Central Role of the TLR/mTOR/PPARγ and NFkB Axes in Burn and
Cressida Mahung1, Shannon M Wallet2,3, Jordan E Jacobs1
1North Carolina Jaycee Burn Center, Department of Surgery, Chapel Hill, NC 27514, USA.
Abstract:
Burn patients are subject to significant acute immune and metabolic dysfunction. Concomitant inhalation injury increases mortality by 20%. In order to identify specific immune and metabolic signaling pathways in burn (B), inhalation (I), and combined burn-inhalation (BI) injury, unbiased nanoString multiplex technology was used to investigate gene expression within peripheral blood mononuclear cells (PBMCs) from burn patients, with and without inhalation injury. PBMCs were collected from 36 injured patients and 12 healthy, non-burned controls within 72 h of injury. mRNA was isolated and hybridized with probes for 1342 genes related to general immunology and cellular metabolism. From these specific gene patterns, specific cellular perturbations and signaling pathways were inferred using robust bioinformatic tools. In both B and BI injuries, elements of mTOR, PPARγ, TLR, and NF-kB signaling pathways were significantly altered within PBMC after injury compared to PBMC from the healthy control group. Using linear regression modeling, (1) DEPTOR, LAMTOR5, PPARγ, and RPTOR significantly correlated with patient BMI; (2) RPTOR significantly correlated with patient length of stay, and (3) MRC1 significantly correlated with the eventual risk of patient mortality. Identification of mediators of this immunometabolic response that can act as biomarkers and/or therapeutic targets could ultimately aid the management of burn patients.
Insights
Burn and inhalation injuries disrupt immune and metabolic pathways. Identifying key genes like DEPTOR and RPTOR in peripheral blood mononuclear cells (PBMCs) may reveal biomarkers for burn patient outcomes.
Area of Science:
- Immunology
- Metabolomics
- Genomics
Background:
- Burn patients experience severe immune and metabolic dysfunction.
- Inhalation injury significantly increases burn patient mortality.
- Understanding immunometabolic signaling is crucial for managing burn injuries.
Purpose of the Study:
- To identify specific immune and metabolic signaling pathways in burn (B), inhalation (I), and combined burn-inhalation (BI) injuries.
- To investigate gene expression in peripheral blood mononuclear cells (PBMCs) of burn patients.
- To correlate gene expression with clinical outcomes like BMI, length of stay, and mortality.
Main Methods:
- Utilized nanoString multiplex technology for unbiased gene expression profiling.
- Analyzed mRNA from PBMCs of 36 injured patients and 12 healthy controls within 72 hours of injury.
- Employed bioinformatic tools to infer cellular perturbations and signaling pathways from gene expression patterns.
Main Results:
- mTOR, PPARγ, TLR, and NF-kB signaling pathways were significantly altered in B and BI injuries compared to controls.
- DEPTOR, LAMTOR5, PPARγ, and RPTOR gene expression correlated with patient BMI.
- RPTOR correlated with length of stay, and MRC1 correlated with mortality risk.
Conclusions:
- Specific immunometabolic signaling pathways are dysregulated in burn and inhalation injuries.
- Certain genes (DEPTOR, LAMTOR5, PPARγ, RPTOR, MRC1) show potential as biomarkers for clinical outcomes.
- Identifying these mediators could lead to improved therapeutic strategies for burn patients.
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