lipoteichoic-acid and Nervous-System-Diseases

Toll-like receptor 2 (TLR2) is a primary sensor for pathogens, including those derived from gram-positive bacteria. It can also mediate the effects of endogenous inflammatory signals such as β-amyloid peptide (Aβ), thus promoting the microglial activation and subsequent neuronal dysfunction, characteristic of chronic neuroinflammatory conditions. More recently, a role for TLR2 has been proposed in the pathogenesis of disorders associated with acute inflammation, including anxiety and depression. The current study aims to characterise the acute effects of the TLR2 agonist lipoteichoic acid (LTA) on microglial activation and neuronal integrity, and to evaluate the influence of LTA exposure on sensitivity to the inflammation and neuronal dysfunction associated with Aβ. Using BV2 and N2a cells as an in vitro model, we highlight that acute exposure to LTA robustly promotes inflammatory cytokine and nitric oxide (NO) production in microglia but also in neurons, similar to that reported under longer-term and chronic inflammatory conditions. Moreover, we find that exposure to LTA can enhance sensitivity to subthreshold Aβ, promoting an 'M1'-like phenotype in microglia and provoking dysregulation of neuronal activity in acute hippocampal slices. Anti-inflammatory agents, including mimetics of brain-derived neurotrophic factor (BDNF), have proven effective at alleviating chronic neuroinflammatory complications. We further examined the effects of 7,8,3-trihydroxyflavone (7,8,3-THF), a small-molecule TrkB agonist, on LTA-induced microglial activation. We report that 7,8,3-THF can significantly ameliorate interleukin (IL)-6 and NO production in LTA-stimulated BV2 cells. Taken together, our findings offer support for exploration of TLR2 as a potential target for therapeutic intervention into acute neuroinflammatory conditions. Moreover we propose that exposure to gram-positive bacterial pathogens may promote sensitivity to the inflammatory changes characteristic of the aged brain.

Topics: Acute Disease; Amyloid beta-Peptides; Animals; Cell Line; Cyclooxygenase 2; Cytokines; Flavones; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice, Inbred C57BL; Microglia; Models, Theoretical; Nervous System Diseases; Neurons; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Receptor, trkB; Teichoic Acids; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha

Lipoteichoic and teichoic acids are components of the cell wall of Streptococcus pneumoniae. A recently developed enzyme immunoassay was used in patients with pneumococcal meningitis to investigate lipoteichoic and teichoic acid concentrations in CSF at the first lumbar puncture in relation to the clinical outcome determined by the Glasgow Outcome Scale. Lipoteichoic and teichoic acid concentrations in CSF were significantly associated with neurologic sequelae and mortality in S. pneumoniae meningitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child, Preschool; Disability Evaluation; Female; Glasgow Coma Scale; Humans; Immunoenzyme Techniques; Infant; Infant, Newborn; Lipopolysaccharides; Male; Meningitis, Pneumococcal; Middle Aged; Nervous System Diseases; Osmolar Concentration; Spinal Puncture; Teichoic Acids