Premium
Highly electronegative low‐density lipoprotein L5 evokes microglial activation and creates a neuroinflammatory stress via Toll‐like receptor 4 signaling
Author(s) -
Yu LiangEn,
Lai ChiouLian,
Lee ChingTien,
Wang JizYuh
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14053
Subject(s) - neuroinflammation , microglia , viability assay , microbiology and biotechnology , chemistry , tumor necrosis factor alpha , oxidative stress , nitric oxide , nitric oxide synthase , signal transduction , neuroprotection , protein kinase b , neurodegeneration , apoptosis , inflammation , pharmacology , biology , immunology , endocrinology , medicine , biochemistry , disease
Atherogenic risk factors, such as hypercholesterolemia, are associated with increased risk of neurodegeneration, especially Alzheimer's dementia. Human plasma electronegative low‐density lipoprotein [ LDL (−)], especially L5, may serve as an important contributing factor. L5 promoting an inflammatory action in atherosclerosis has been extensively studied. However, the role of L5 in inducing neuroinflammation remains unknown. Here, we examined the impact of L5 on immune activation and cell viability in cultured BV ‐2 microglia. BV ‐2 cells treated with lipopolysaccharide or human LDL s (L1, L5, or ox LDL ) were subjected to molecular/biochemical assays for measuring microglial activation, levels of inflammatory factors, and cell survival. A transwell BV ‐2/N2a co‐culture was used to assess N2a cell viability following BV ‐2 cell exposure to L5. We found that L5 enables the activation of microglia and elicits an inflammatory response, as evidenced by increased oxygen/nitrogen free radicals (nitric oxide, reactive oxygen species, and peroxides), elevated tumor necrosis factor‐α levels, decreased basal interleukin‐10 levels, and augmented production of pro‐inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase‐2). L5 also triggered BV ‐2 cell death primarily via apoptosis. These effects were markedly disrupted by the application of signaling pathway inhibitors, thus demonstrating that L5 interacts with Toll‐like receptor 4 to modulate multiple pathways, including MAPK s, PI 3K/Akt, and NF ‐κB. Decreased N2a cell viability in a transwell co‐culture was mainly ascribed to L5‐induced BV ‐2 cell activation. Together, our data suggest that L5 creates a neuroinflammatory stress via microglial Toll‐like receptor 4, thereby leading to the death of BV ‐2 microglia and coexistent N2a cells. Atherogenic L5 possibly contributes to neuroinflammation‐related neurodegeneration.