期刊
IMMUNOLOGY
卷 144, 期 3, 页码 365-373出版社
WILEY
DOI: 10.1111/imm.12443
关键词
neuroinflammation; neuroprogression; reactive oxygen species; signal transduction; transcription factors
类别
资金
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- Commission of European Communities [22963]
- Johnson & Johnson-King's College London
- Medical Research Council [G108/603, MR/J002739/1] Funding Source: researchfish
- MRC [MR/J002739/1, G108/603] Funding Source: UKRI
Emerging evidence suggests a significant role for inflammation and oxidative stress as main contributors to the neuroprogression that is observed in major depressive disorder (MDD), where patients show increased inflammatory and oxidative stress biomarkers. The process of neuroprogression includes stage-related neurodegeneration, cell death, reduced neurogenesis, reduced neuronal plasticity and increased autoimmune responses. Oxidative stress is a consequence of the biological imbalance between reactive oxygen species (ROS) and antioxidants, leading to the alteration of biomolecules and the loss of control of the intracellular redox-related signalling pathways. ROS serve as crucial secondary messengers in signal transduction and significantly affect inflammatory pathways by activating nuclear factor-kappa B and mitogen-activated protein kinase family stress kinases. When present in excess, ROS inflict damage, affecting cellular constituents with the formation of pro-inflammatory molecules, such as malondialdehyde, 4-hydroxynonenal, neoepitopes and damage-associated molecular patterns promoting immune response, and ultimately leading to cell death. The failure of cells to adapt to the changes in redox homeostasis and the subsequent cell death, together with the damage caused by inflammatory mediators, have been considered as major causes of neuroprogression and hence MDD. Both an activated immune-inflammatory system and increased oxidative stress act synergistically, complicating our understanding of the pathogenesis of depression. The cascade of antioxidative and inflammatory events is orchestrated by several transcription factors, with nuclear factor (erythroid-derived 2)-like 2 and nuclear factor-jB having particular relevance to MDD. This review focuses on potential molecular mechanisms through which impaired redox homeostasis and neuroinflammation can affect the neuronal environment and contribute to depression.
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