Diverse action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood-brain barrier disruption, and anxiety in mice

Abstract

Microbial metabolites are known to affect immune system, brain, and behavior via activation of pattern recognition receptors such as Toll-like receptor 4 (TLR4). Unlike the effect of the TLR4 agonist lipopolysaccharide (LPS), the role of other TLR agonists in immune-brain communication is insufficiently understood. We therefore hypothesized that the TLR2 agonist lipoteichoic acid (LTA) causes immune activation in the periphery and brain, stimulates the hypothalamic-pituitary-adrenal (HPA) axis and has an adverse effect on blood-brain barrier (BBB) and emotional behavior. Since LTA preparations may be contaminated by LPS, an extract of LTA (LTA), purified LTA (LTA), and pure LPS (LPS) were compared with each other in their effects on molecular and behavioral parameters 3h after intraperitoneal (i.p.) injection to male C57BL/6N mice. The LTA (20mg/kg) induced anxiety-related behavior in the open field test, enhanced the circulating levels of particular cytokines and the cerebral expression of cytokine mRNA, and blunted the cerebral expression of tight junction protein mRNA. A dose of LPS matching the amount of endotoxin/LPS contaminating the LTA reproduced several of the molecular and behavioral effects of LTA. LTA (20mg/kg) increased plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 and interferon-γ, and enhanced the transcription of TNF-α, interleukin-1β and other cytokines in the amygdala and prefrontal cortex. These neuroinflammatory effects of LTA were associated with transcriptional down-regulation of tight junction-associated proteins (claudin 5, occludin) in the brain. LTA also enhanced circulating corticosterone, but failed to alter locomotor and anxiety-related behavior in the open field test. These data disclose that TLR2 agonism by LTA causes peripheral immune activation and initiates neuroinflammatory processes in the brain that are associated with down-regulation of BBB components and activation of the HPA axis, although emotional behavior (anxiety) is not affected. The results obtained with an LTA preparation contaminated with LPS hint at a facilitatory interaction between TLR2 and TLR4, the adverse impact of which on long-term neuroinflammation, disruption of the BBB and mental health warrants further analysis.

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

“…As reported previously [1,18,19], LPS enhanced circulating cytokine levels in a pattern typical of TLR4-mediated immune stimulation. The LPS-induced rise of circulating cytokines seen 3 h post-injection was transient because 21 h post-LPS the plasma levels of the measured cytokines, except MCP-1, were no longer elevated.…”

“…Cytokine levels in the plasma were analyzed with a multiplex immunoassay as described previously [18]. ProcartaPlex™ immunoassays (eBioscience, San Diego, CA, USA) were used to evaluate cytokine concentrations in plasma samples according to the manufacturer's specifications and as previously described [18]. Cytokines were measured in duplicates, and fluorescent signals were quantified with the Bio-Plex 200 multiplex suspension array system and Luminex® xMAP® technology.…”

Association of gut microbial communities with plasma lipopolysaccharide-binding protein (LBP) in premenopausal women

“…Alternatively, we did not observe any differences in LTA synthesis genes across LBP tertiles. While previous studies have shown that activation of cellular responses by LTA, a cell wall component of gram-positive bacteria, is enhanced by LBP [60,61], no previous studies have examined the association between LTA genes and circulating LBP levels; current study results suggest that the functional potential of genes-related LTA synthesis is not associated with those responsible for LPS synthesis.…”

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

“…Other WT mice were treated with a single IP injection of lipoteichoic acid (LTA, 20 mg/kg for 3 hours) to activate TLR2 or ultrapure lipopolysaccharide (LPS, 5 mg/kg for 24 hours) to activate TLR4. These treatments have been used by other authors previously …”