title: Toll-like receptor 2 and nucleotide-binding oligomerization domain-2 play divergent roles in the recognition of gut-derived lactobacilli and bifidobacteria in dendritic cells.
abstract: The gut microbiota is vital in the maintenance of homeostasis in the gut immune system. Its diversity and composition play major roles in relation to allergies and inflammatory bowel diseases, and administration of lactic acid bacteria (LAB), such as lactobacilli and bifidobacteria, has positive effects on these pathologies. However, the mechanisms behind the beneficial effects are largely unknown. Here we reveal divergent roles played by Toll-like receptor-2 (TLR2) and nucleotide-binding oligomerization domain-2 (NOD2) in dendritic cell (DC) recognition of LAB. Murine bone-marrow-derived DC lacking NOD2 produce higher levels of interleukin-10 (IL-10) and reduced levels of IL-12 and tumour necrosis factor-alpha (TNF-alpha) in response to LAB. This indicates that peptidoglycan is partly responsible for the T helper type 1 skewing effect of certain LAB. Dendritic cells that are TLR2-/- produce less IL-12 and TNF-alpha and more IL-10 in response to some strains of lactobacilli, while they produce more IL-12 and less IL-10 in response to bifidobacteria. The same tendency was found in human monocyte-derived DC. We have previously reported that the weak IL-12-inducing and TNF-alpha-inducing bifidobacteria inhibit the T helper type 1 skewing effect induced by strong immunostimulatory lactobacilli. Here we show that this immunoinhibitory effect of bifidobacteria is dependent on TLR2 and independent of NOD2. Moreover, independently of the cytokine pattern induced by intact LAB, cell wall fractions of all LAB, as well as synthetic lipoproteins possess immunoinhibitory capacities in both human and murine DC. These novel findings suggest that LAB act as immunoregulators through interaction of lipoprotein with TLR2 and as immunostimulators through interaction of peptidoglycan with NOD2.
authors.affiliation: BioCentrum-DTU, Nutritional Immunology Group, Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. lhz@biocentrum.dtu.dk
authors.forename: Louise Hjerrild
authors.initials: LH
authors.lastname: Zeuthen
authors.forename: Lisbeth Nielsen
authors.initials: LN
authors.lastname: Fink
authors.forename: Hanne
authors.initials: H
authors.lastname: Frøkiaer
mesh_terms: D000818:Animals; D001644:Bifidobacterium / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002473:Cell Wall / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007778:Lactobacillus / Q000145:classification / Q000276:immunology*; D007779:Lactobacillus acidophilus / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology; D013045:Species Specificity; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D037181:Lectins, C-Type; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin