title: 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 (LTAextract), purified LTA (LTApure), and pure LPS (LPSultrapure) 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 LTAextract(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 LPSultrapurematching the amount of endotoxin/LPS contaminating the LTAextractreproduced several of the molecular and behavioral effects of LTAextract. LTApure(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 LTApurewere associated with transcriptional down-regulation of tight junction-associated proteins (claudin 5, occludin) in the brain. LTApurealso 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.
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Mayerhofer
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Fröhlich
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Reichmann
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Aitak
authors.initials: A
authors.lastname: Farzi
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
authors.forename: Nora
authors.initials: N
authors.lastname: Kogelnik
authors.affiliation: Center for Medical Research, Medical University of Graz, Stiftingtalstrasse 24/1, 8010 Graz, Austria.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, Austria. Electronic address: peter.holzer@medunigraz.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D007371:Interferon-gamma / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D013682:Teichoic Acids / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D007371:Interferon-gamma
keywords: Anxiety; Brain; Corticosterone; Cytokines; Lipopolysaccharide; Lipoteichoic acid; Neuroinflammation; Tight junction-associated proteins; Toll-like receptors