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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2019-12, Vol.97 (12), p.1627-1641
• Main Authors: Bhowmick, Saurav, D’Mello, Veera, Caruso, Danielle, Abdul-Muneer, P. M.
• Format: Article
• Language: English
• Subjects: Antioxidants; Apoptosis; Biomedical and Life Sciences; Biomedicine; Brain; Cell death; Human Genetics; Inflammation; Inflammatory response; Internal Medicine; Molecular Medicine; Neurodegeneration; Nitric oxide; Original Article; Oxidative stress; Transforming growth factor-b1; Traumatic brain injury
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-019-01851-4

Recent studies from our group and others have demonstrated that oxidative stress, Ca 2+ 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.