PMID- 28886135
OWN - NLM
STAT- MEDLINE
DCOM- 20171018
LR  - 20220430
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 9
DP  - 2017
TI  - 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.
PG  - e0184164
LID - 10.1371/journal.pone.0184164 [doi]
LID - e0184164
AB  - 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.
FAU - Eitas, Timothy K
AU  - Eitas TK
AUID- ORCID: 0000-0001-6925-2618
AD  - Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit, 
      Glaxosmithkline Pharmaceuticals, Upper Providence, Pennsylvania, United States of 
      America.
FAU - Stepp, Wesley H
AU  - Stepp WH
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Sjeklocha, Lucas
AU  - Sjeklocha L
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Long, Clayton V
AU  - Long CV
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Riley, Caitlin
AU  - Riley C
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Callahan, James
AU  - Callahan J
AD  - Stress and Repair Discovery Performance Unit, Respiratory Therapy Area Unit, 
      Glaxosmithkline Pharmaceuticals, Upper Merion, Pennsylvania, United States of 
      America.
FAU - Sanchez, Yolanda
AU  - Sanchez Y
AD  - Stress and Repair Discovery Performance Unit, Respiratory Therapy Area Unit, 
      Glaxosmithkline Pharmaceuticals, Upper Merion, Pennsylvania, United States of 
      America.
FAU - Gough, Peter
AU  - Gough P
AD  - Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit, 
      Glaxosmithkline Pharmaceuticals, Upper Providence, Pennsylvania, United States of 
      America.
FAU - Knowlin, Laquanda
AU  - Knowlin L
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - van Duin, David
AU  - van Duin D
AD  - Division of Infectious Diseases, University of North Carolina at Chapel Hill, 
      Chapel Hill, North Carolina, United States of America.
FAU - Ortiz-Pujols, Shiara
AU  - Ortiz-Pujols S
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Jones, Samuel W
AU  - Jones SW
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Maile, Robert
AU  - Maile R
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
FAU - Hong, Zhi
AU  - Hong Z
AD  - Infectious Diseases Therapy Area Unit, Glaxosmithkline Pharmaceuticals, Research 
      Triangle Park, Durham, North Carolina, United States of America.
FAU - Berger, Scott
AU  - Berger S
AD  - Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit, 
      Glaxosmithkline Pharmaceuticals, Upper Providence, Pennsylvania, United States of 
      America.
FAU - Cairns, Bruce A
AU  - Cairns BA
AD  - Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, United States of America.
LA  - eng
GR  - K08 GM109106/GM/NIGMS NIH HHS/United States
GR  - T32 GM008450/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170908
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cytokines)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
EIN - PLoS One. 2017 Nov 2;12 (11):e0187785. PMID: 29095909
MH  - Adult
MH  - Burns/*immunology/*metabolism/mortality/therapy
MH  - Chemokine CCL2/biosynthesis
MH  - Cohort Studies
MH  - Cytokines/*biosynthesis
MH  - Female
MH  - Humans
MH  - *Immunity, Innate
MH  - Leukocytes, Mononuclear/immunology/metabolism
MH  - Lymphocytes/*immunology/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Monocytes/*immunology/*metabolism
MH  - NF-E2-Related Factor 2/*metabolism
PMC - PMC5590883
COIS- Competing Interests: The funder provided support in the form of salaries for 
      authors (TKE, JC, YS, PG, ZH, SB), but did not have any additional role in the 
      study design, data collection and analysis, decision to publish, or preparation 
      of the manuscript. The specific roles of these authors are articulated in the 
      'author contributions' section. TKE, JC, YS, PG, ZH, and SB are employees of 
      GlaxoSmithKline. This commercial affiliation does not alter our adherence to PLOS 
      ONE policies on sharing data and materials.
EDAT- 2017/09/09 06:00
MHDA- 2017/10/19 06:00
PMCR- 2017/09/08
CRDT- 2017/09/09 06:00
PHST- 2017/04/12 00:00 [received]
PHST- 2017/08/19 00:00 [accepted]
PHST- 2017/09/09 06:00 [entrez]
PHST- 2017/09/09 06:00 [pubmed]
PHST- 2017/10/19 06:00 [medline]
PHST- 2017/09/08 00:00 [pmc-release]
AID - PONE-D-17-14253 [pii]
AID - 10.1371/journal.pone.0184164 [doi]
PST - epublish
SO  - PLoS One. 2017 Sep 8;12(9):e0184164. doi: 10.1371/journal.pone.0184164. 
      eCollection 2017.