Toll-Like Receptor 4 or 2 Agonists Decrease Allergic Inflammation

Abstract

Toll-like receptors (TLRs) recognize highly conserved microbial molecular patterns, such as found in endotoxin. This study tested whether TLR4 and TLR2 stimulation in vivo would modulate subsequent adaptive (allergic) immune responses. We analyzed the effects of pulmonary administration of a TLR4 agonist, lipid A (LpA), and two TLR2 agonists, peptidoglycan (Ppg) and PamCys, in a murine model of allergic inflammation. The TLR agonists were administered during allergen sensitization or challenge. Both TLR agonists decreased the allergen-induced pulmonary recruitment of eosinophils when administered at sensitization or challenge. When given before sensitization, the TLR4 and TLR2 agonists decreased additional allergen-induced parameters of inflammation (pulmonary eosinophilia, bronchoalveolar lavage IL-13, total serum IgE, and airway hyperresponsiveness). Interestingly, TLR4 and TLR2 agonists decreased the number of CD4+ cells in the lung. Also, at the site of local allergen stimulation, the draining thoracic lymph nodes, allergen-induced lymphocyte proliferation, and IL-13 secretion were decreased by administration of LpA and Ppg. These data provide a distinct example of the modulation of adaptive (allergic) responses by non-antigen-dependent stimuli. Our findings also demonstrate that both TLR4 and TLR2 agonists decrease allergic responses, supporting the concept that exposure to bacterial components under defined conditions may protect against allergic disease.

Children's Immunology, what can we learn from animal studies (2): Modulation of systemic Th1/Th2 immune response in infant mice after prenatal exposure to low-level toluene and tolllike receptor (TLR) 2 ligand

“…Intratracheally administered PGN (75 μg) also primarily induces IL-13 secretion in BAL from adult BALB/c mice (Schaub et al, 2004). Our results may differ from those of Velasco et al (2005), possibly because of the different route of administration, PGN dose, strain and age of animals and measurement parameters used.…”

“…TLR ligands such as PGN, LPS and CpG-ODN, modulate the immune response via TLR-2, -4 and -9 mediated pathways, respectively, particularly in the direction of Th1 dominance (Eisenbarth et al, 2002;Vollmer et al, 2004;Velasco et al, 2005). It has been reported that intratracheal instillation of PGN (225 μg) 13, a Th2-type cytokine, in the BAL from OVA-stimulated adult C57BL/6 mice (Velasco et al, 2005). Intratracheally administered PGN (75 μg) also primarily induces IL-13 secretion in BAL from adult BALB/c mice (Schaub et al, 2004).…”

“…Because the Th2 arm is negatively regulated by Th1, some bacteria and their components which stimulate the Th1 response suppress the Th2 response and associated IgE production. For example, it has been reported that ligands for Tolllike receptors (TLR) 2, 4, or 9, such as peptidoglycan (PGN), lipopolysaccharide (LPS) and CpG-oligodeoxynucleotides (CPG-ODN) modulate Th2-driven allergic immune responses in animals (Velasco et al, 2005;Eisenbarth et al, 2002;Vollmer et al, 2004). In the present study, we used PGN from Staphylococcus aureus in order to determine whether cell-wall components of gram-positive bacterial modulate Th1/Th2 immunity in offspring from pregnant mice exposed to toluene.…”

Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells

“…For example, upregulation of TLR2-expression has been shown in farm children at school age 4 , and TLR2/TLR4-upregulation was strongly determined by maternal exposure to stables during pregnancy 3 . These human data were supported by murine studies, demonstrating decreased allergic responses following TLR2/TLR4 stimulation 5 .…”

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

“…We provide evidence that cystatin protects from inflammation in a systemic fashion, as reflected by its effects on remarkably different compartments, such as the lung and the gut. Moreover, the protein inhibits Th2-related as well as macrophage-related inflammation, which stands in stark contrast to the effect of TLR2 and TLR4 agonists of bacterial origin that have recently been shown to downregulate Th2-driven allergic responses in mouse models (56,57). These components act through stimulation of Th1 responses, as evidenced by elevated production of IFN-␥ and other Th1 cytokines, which is clearly not the case for filarial cystatin.…”