Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death

J Mol Med (Berl). 2019 Dec;97(12):1627-1641. doi: 10.1007/s00109-019-01851-4. Epub 2019 Nov 22.

Abstract

Recent studies from our group and others have demonstrated that oxidative stress, Ca2+ signaling, and neuroinflammation are major mechanisms contributing to post-traumatic neurodegeneration. The present study investigated the mechanisms of regulation of nuclear factor E2-related factor 2 (Nrf2) and its role in regulating antioxidant genes and oxidative stress-induced neuroinflammation and neurodegeneration following TBI. Nrf2 transcriptional system is the major regulator of endogenous defense mechanisms operating within the cells. Wild-type (Nrf2+/+) and Nrf2-deficient mice (Nrf2-/-) were subjected to 15 psi fluid percussion injury and demonstrated the regulatory role of Nrf2 in the expression antioxidant genes and oxidative stress, neuroinflammation, and cell death. Immunohistochemistry, q-RT-PCR, and western blotting techniques detected downregulation of Nrf2 and antioxidant proteins such as HO-1, GPx1, GSTm1, and NQO1 in mouse brain samples. Further, our study demonstrated that the downregulation of Nrf2 and antioxidant genes in TBI correlated with the induction of free radical-generating enzyme NADPH oxidase 1 and inducible nitric oxide synthase and their corresponding oxidative/nitrosative stress markers 4-hydroxynonenal and 3-nitrotyrosine. The decrease in Nrf2 with subsequent increase in oxidative stress markers led to the activation of MMP3/9, TGF-β1, and NF-kB that further led to neuroinflammation and apoptosis. The absence of Nrf2 function in mice resulted in exacerbated brain injury as shown by the increased oxidative stress markers, pro-inflammatory cytokines, and apoptosis markers at 24 h after TBI. In conclusion, this study could establish the significance of Nrf2 in transforming into a novel preventive approach against the pathophysiology of TBI. KEY MESSAGES: • Traumatic brain injury impairs Nrf2 signaling in mouse. • Nrf2-mediated activation of antioxidant genes are altered after TBI. • Impairment of Nrf2 signaling leads to oxidative stress. • TBI-induced downregulation of Nrf2 activates MMPs, TGF-β1, and NF-kB. • Nrf2 regulates neuroinflammation and apoptotic cell death in TB.

Keywords: Antioxidant genes; Neurodegeneration; Neuroinflammation; Nrf2 signaling; Oxidative stress; Traumatic brain injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Apoptosis* / genetics
  • Brain / cytology
  • Brain / metabolism*
  • Brain / physiopathology
  • Brain Injuries, Traumatic / genetics
  • Brain Injuries, Traumatic / metabolism*
  • Brain Injuries, Traumatic / physiopathology
  • Down-Regulation / genetics
  • Inflammation / genetics
  • Inflammation / metabolism
  • Male
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADPH Oxidase 1 / metabolism
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / metabolism
  • Oxidative Stress* / genetics
  • Phosphorylation
  • Signal Transduction / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antioxidants
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Transforming Growth Factor beta1
  • Nitric Oxide Synthase
  • NADPH Oxidase 1
  • NOX1 protein, mouse
  • Matrix Metalloproteinase 3
  • Mmp3 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse