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

Summary 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‐α (TNF‐α) 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‐α 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‐α‐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.

Construction and Immunological Evaluation of Dual Cell Surface Display of HIV-1 Gag and Salmonella enterica Serovar Typhimurium FliC in Lactobacillus acidophilus for Vaccine Delivery

“…The bacterial stimulation caused maturation and cytokine production of the DCs, regardless of the recombinant cell surface antigens. Previous studies showed that maturation and the cytokine responses of mouse or human DCs were induced by lactobacilli in a species/strain-dependent manner (7,9,30,42). This is apparently the result of variation of the MAMP composition and structure (13,24,33).…”

Tetragenococcus halophilus MN45 Isolated from Miso Inhibits IgE Production

“…1). It has been reported that the intact cell structure of LAB is an important element in its immunomodulatory activity and that the mature bacterial cells in the stationary phase induce more Th1-type cytokines than the immature cells in the logarithmic growth phase (Shida et al, 2006;Zeuthen et al, 2008;Sashihara et al, 2007). In our examination, there was no difference in Th1-type cytokine induction between MN45 cultured over a long period of time (35 days) and a short period of time (2 days).…”

“…As the LAB used for screening experiments were cultured for 7 days, the cultures contained not only live bacteria but also dead bacteria, and bacteriolysis was assumed to have occurred. It has been reported that the immunomodulatory activity of LAB contributes to the intact structure of the cell (Zeuthen et al, 2008). Therefore, the culture time may influence the cytokine-induction activity of MN45.…”

Immunobiotic Lactobacillus jensenii Elicits Anti-Inflammatory Activity in Porcine Intestinal Epithelial Cells by Modulating Negative Regulators of the Toll-Like Receptor Signaling Pathway

“…However, TLR2 also seems to be involved in some anti-inflammatory effects of probiotics. Immunobiotics can inhibit IL-12 production by macrophages (33) and dendritic cells (47) by TLR2-mediated recognition of lipoproteins and insoluble cell walls. Moreover, TLR2 can induce tolerance of LPS that is referred to as heterotolerance or cross-tolerance (26).…”