Multiplexed Human Gene Expression Analysis Reveals a Central Role of the TLR/mTOR/PPARγ and NFkB Axes in Burn and Inhalation Injury-Induced Changes in Systemic Immunometabolism and Long-Term Patient Outcomes

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.

PPARG stimulation restored lung mRNA expression of core clock, inflammation‐ and metabolism‐related genes disrupted by reversed feeding in male mice

“…A remarkable increase was observed in the midnight and noon expression of Nfe2l2 and Cxcl5 mRNA with pro‐inflammatory properties. NFκB axis has great importance for lung immunometabolism and injury (Mahung et al, 2022 ; Soto et al, 2020 ; Tang et al, 2018 ). NFκB through TNF‐alpha can stimulate cells to upregulate several pro‐inflammatory mediators such as neutrophilic chemokine CXCL5 (Kuret et al, 2022 ).…”

Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction

“…Downregulation of P70S6K after MSC-EV treatment compared to untreated mice also suggests that mTOR activation has been reduced ( 67 ). We have shown that the mTOR/PPARγ axis is partly responsible for the acute and chronic (analogous to DEARE) immune dysfunction in burn injury ( 68 – 70 ), and experiments are underway to determine if MSC-EV can modulate this response in an mTOR-dependent fashion. It is therefore tempting to speculate that a key component of the reprogramming capacity of MSC-EVs is mTOR dependent.…”