Journal article
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
PloS one, Vol.12(9), pp.e0184164-e0184164
09/08/2017
DOI: 10.1371/journal.pone.0184164
PMCID: PMC5590883
PMID: 28886135
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.
Details
- Title: Subtitle
- 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
- Creators
- Timothy K Eitas - GlaxoSmithKlineWesley H Stepp - University of North Carolina at Chapel HillLucas Sjeklocha - University of North Carolina at Chapel HillClayton V Long - University of North Carolina at Chapel HillCaitlin Riley - University of North Carolina at Chapel HillJames Callahan - GlaxoSmithKlineYolanda Sanchez - GlaxoSmithKlinePeter Gough - GlaxoSmithKlineLaquanda Knowlin - University of North Carolina at Chapel HillDavid van Duin - University of North Carolina at Chapel HillShiara Ortiz-Pujols - University of North Carolina at Chapel HillSamuel W Jones - University of North Carolina at Chapel HillRobert Maile - University of North Carolina at Chapel HillZhi Hong - Research Triangle Park FoundationScott Berger - GlaxoSmithKlineBruce A Cairns - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.12(9), pp.e0184164-e0184164
- DOI
- 10.1371/journal.pone.0184164
- PMID
- 28886135
- PMCID
- PMC5590883
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Grant note
- T32 GM008450 / NIGMS NIH HHS K08 GM109106 / NIGMS NIH HHS
- Language
- English
- Date published
- 09/08/2017
- Academic Unit
- Surgery
- Record Identifier
- 9984755390602771
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