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Inflammatory stress induces a biphasic Nrf2 activation in neuronal cells
Author(s) -
Krepel Stacey A,
O'Hara Lars,
Mangum Sally,
Hogan Mary B,
Kuhn Thomas B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.779.3
Subject(s) - oxidative stress , chromosomal translocation , keap1 , chemistry , tumor necrosis factor alpha , nucleus , transcription factor , microbiology and biotechnology , cytosol , medicine , endocrinology , biology , biochemistry , gene , enzyme
Persistent inflammatory and oxidative stress (IOS) is largely responsible for the progressive loss of neuronal integrity and connectivity underlying the continuous decline of cognitive function associated with most chronic CNS disorders as well as normal aging. The transcription factor Nrf2 plays a pivotal role in the antioxidant defense of non‐neuronal and neuronal cells. Nrf2 remains sequestered in the cytosol of cells under basal conditions tightly bound to its repressor Keap1. Upon oxidative stress, Nrf2 dissociates from Keap1 and translocates into the nucleus to stimulate transcription of antioxidant defense mechanisms. It is not yet clear how duration and extent of IOS impact Nrf2 activation and nuclear translocation in neuronal cells. Exposure of SH‐SY5Y human neuroblastoma to 200 ng/ml TNFa caused a time dependent Nrf2 translocation (2 fold increase) into the nucleus peaking 4 h after addition. However, nuclear Nrf2 decreased and remained at 50% of peak maximum for a prolonged time period. A presence of 50 ng/ml TNFa resulted in the highest accumulation of Nrf2 in the nucleus—giving a 53% increase of translocation relative to the control—compared to higher concentrations (100 to 400 ng/ml) even over prolonged periods of time. Immunocytochemistry against Nrf2 corroborated these findings. Additionally, prolonged exposure of SH‐SY5Y cells to TNFa (24 h) at concentrations 200 ng/mL or higher resulted in significant cell death due to oxidative stress. At high concentrations of 200 ng/mL and 400 ng/mL, even short treatment times of 1 hour resulted in the respective 52% and 112% reduction in Nrf2 translocation relative to the peak translocation achieved at 50 ng/mL. Together these findings suggest that Nrf2‐mediated antioxidant defenses in response to high concentrations of either chronic or acute TNFa exposure were insufficient and even depressed. One of the many health benefits of nutrition rests on the capacity of distinct botanicals, in particular polyphenols, to directly act on biochemical mechanisms rather than through passive antioxidant capacities. We demonstrated that supplementation of SH‐SY5Y neuroblastoma cells with extracts obtained from Alaska wild bog blueberries (5 mg/ml) increased neuronal viability in the prolonged presence of 200 ng/mL TNFa. Surprisingly, blueberry extracts prevent Nrf2 nuclear accumulation upon exposure to TNFa. Understanding the regulation of Nrf2 through botanicals could provide vital insight for developing neuroprotective strategies applicable to an array of neurodegenerative diseases. Support or Funding Information Supported in part by NIH grants RL56M118990, 1UL16M18991, TL4GM118992, and generous donations from the Alzheimer's Resources of Alaska. The work is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health