Abstract
Burn patients suffer from immunological dysfunction for which there are currently no successful interventions. Similar to previous observations, we find that burn shock patients (≥15% Total Burn Surface Area (TBSA) injury) have elevated levels of the innate immune cytokines Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1)/CC-motif Chemokine Ligand 2(CCL2) early after hospital admission (0–48 Hours Post-hospital Admission (HPA). Functional immune assays with patient Peripheral Blood Mononuclear Cells (PBMCs) revealed that burn shock patients (≥15% TBSA) produced elevated levels of MCP-1/CCL2 after innate immune stimulation ex vivo relative to mild burn patients. Interestingly, treatment of patient PBMCs with the Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) agonist, CDDO-Me(bardoxolone methyl), reduced MCP-1 production but not IL-6 or Interleukin-10 (IL-10) secretion. In enriched monocytes from healthy donors, CDDO-Me(bardoxolone methyl) also reduced LPS-induced MCP1/CCL2 production but did not alter IL-6 or IL-10 secretion. Similar immunomodulatory effects were observed with Compound 7, which activates the NRF2 pathway through a different and non-covalent Mechanism Of Action (MOA). Hence, our findings with CDDO-Me(bardoxolone methyl) and Compound 7 are likely to reflect a generalizable aspect of NRF2 activation. These observed effects were not specific to LPS-induced immune responses, as NRF2 activation also reduced MCP-1/CCL2 production after stimulation with IL-6. Pharmacological NRF2 activation reduced Mcp-1/Ccl2 transcript accumulation without inhibiting either Il-6 or Il-10 transcript levels. Hence, we describe a novel aspect of NRF2 activation that may contribute to the beneficial effects of NRF2 agonists during disease. Our work also demonstrates that the NRF2 pathway is retained and can be modulated to regulate important immunomodulatory functions in burn patient immune cells.
Highlights
Thermal injuries cause approximately 300,000 human deaths per year worldwide and are among the most expensive traumatic injuries due to long-term hospitalization and wound treatment [1, 2]
We evaluated if treatment of patient Peripheral Blood Mononuclear Cells (PBMCs) with the Nuclear Factor-Erythroid-2-Related Factor (NRF2) agonist, CDDO-Me(bardoxolone methyl), could lead to functional immune changes
The analysis was expanded across the burn patient cohort and we found that treatment of PBMCs with CDDO-Me(bardoxolone methyl) significantly reduced LPS-induced Monocyte Chemoattractant Protein-1 (MCP-1) production but had no distinct effects on either IL-6 or IL-10 secretion (Fig 3A and 3C)
Summary
Thermal injuries cause approximately 300,000 human deaths per year worldwide and are among the most expensive traumatic injuries due to long-term hospitalization and wound treatment [1, 2]. Two major aspects of burn injury are stress-associated pathophysiological changes and mis-regulated inflammatory responses. Studies with Nrf2-/- mice have shown that the loss of Nrf alters inflammatory cytokine production such as Tumor Necrosis Factor-Alpha (TNF-α) and Interleukin 1-beta (IL-1β) in murine fibroblasts and macrophages, respectively [8, 9]. These in vitro findings correlate with changes in inflammatory mediator production in vivo during models of sepsis, peritonitis, and burn injury [8,9,10]. Nrf2-/- deficient peritoneal macrophages produce elevated amounts of Monocyte Chemoattractant Protein-1 (MCP-1) [11]
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