Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mayerhofer, R.
Diverse action of bacterial metabolites on immune activation, brain, and behavior
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gorkiewicz Gregor
- Holzer Peter
- Sattler Wolfgang
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- Abstract:
- Pattern recognition receptors (PRRs) are a crucial factor of the first-boarder defense against invasion by microbes. One broadly studied member of the PRRs is the lipopolysaccharide (LPS)-recognizing Toll-like receptor 4 (TLR4) which stimulates not only the peripheral immune system when activated, but affects brain and behavior. While the effects of LPS on the communication of the immune system and the brain are well understood, effects of other TLR agonists are insufficiently studied. Therefore, the current study aimed to elucidate the wide-ranging effects of the TLR2 stimulating bacterial cell-wall compound lipoteichoic acid (LTA) and hypothesized that LTA leads to immune activation in periphery and brain, activates the hypothalamic-pituitary-adrenal (HPA) axis and affects behavior as well as the integrity of the blood-brain barrier (BBB). Since commercially available LTA is often found to be contaminated with LPS that might be the true cause of LTA effects studied thus far, an extract of LTA (LTAextract), purified LTA (LTApure), and pure LPS (LPSultrapure) were studied with emphasis on their effects 3 h following intraperitoneal (i.p.) injection to male C57BL/6N mice. To assess the purity and specificity of the TLR2 and TLR4 stimulating compounds under study, HEK-Blue® reporter cell assay as well as TAK-242, a TLR4 antagonist, were used. LTAextract (20 mg/kg) showed adverse effects on behavior in the open field and affected molecular parameters, as it induced anxiety-like behavior and raised cytokine levels in the peripheral circulation and cytokine mRNA expression in the brain. Tight junction-associated proteins were down-regulated in their expression on mRNA level. By measuring endotoxin/LPS contamination of LTAextract the corresponding LPSultrapure dose was determined and used to reproduce numerous effects of LTAextract. In contrast, although effective in elevating corticosterone levels within the periphery, LTApure (20 mg/kg) failed to induce anxiety-like behavior and change locomotor activity in the open field. Furthermore, LTApure affected transcription of tight junction-associated proteins, namely claudin 5 and occludin in the brain while upregulating transcription of tumor necrosis factor-a (TNF-a) and interleukin-1ß (IL-1 ß), among other cytokines, in the prefrontal cortex and amygdala. Concerning circulating cytokines, LTApure elevated interleukin-6 (IL-6), TNF-a, and interferon-¿ (IFN- ¿). 6 Taken together, this study provides a broader insight into the effects of LTA acting on TLR2. These effects include stimulation of the peripheral immune system and induction of neuroinflammatory processes within the brain that go along with reduced mRNA expression of BBB tight-junction constituents as well as the activation of the HPA axis. As LTAextract showed more adverse effects when compared to LTApure, including the induction of anxiety-like behavior among others, a facilitatory interaction of LTR2 and TLR4 activation by endotoxin contamination of LTAextract is assumed. These data inform further studies to elucidate possible long-term inflammatory effects in the brain, disturbance of the integrity of the BBB as well as effects on mental health.