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Dietary N-Glycans from Bovine Lactoferrin and TLR Modulation.

ABSTRACT: SCOPE:Bovine lactoferrin (bLF) is an ingredient of food supplements and infant formulas given its antimicrobial and antiviral properties. We modified bLF enzymatically to alter its N-glycosylation and to isolate the glycan chains. The aims of this study include (1) to evaluate whether such derivates induce responses via pattern recognition receptors namely Toll-like receptors (TLRs) and (2) to relate those responses to their different glycosylation profiles. METHODS AND RESULTS:The unmodified and modified bLF fractions are incubated with reporter cell lines expressing pattern recognition receptors. Afterwards, we screen for TLRs and analyze for nuclear factor kappa-light-chain enhancer of activated B cells (NF-?B) activation. Activation of reporter cell lines show that signaling is highly dependent on TLRs. The activation pattern of bLF is reduced with the desialylated form and increased with the demannosylated form. In reporter cells for TLR, bLF activate TLR-4 and inhibit TLR-3. The isolated glycans from bLF inhibit TLR-8. TLR-2, TLR-5, TLR-7, and TLR-9 are not significantly altered. CONCLUSION:The profile of glycosylation is key for the biological activity of bLF. By understanding how this affects the human defense responses, the bLF glycan profile can be modified to enhance its immunomodulatory effects when used as a dietary ingredient.

SUBMITTER: Figueroa-Lozano S

PROVIDER: S-EPMC6120133 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Dietary N-Glycans from Bovine Lactoferrin and TLR Modulation.

Figueroa-Lozano Susana S Valk-Weeber Rivca L RL van Leeuwen Sander S SS Dijkhuizen Lubbert L de Vos Paul P

Molecular nutrition & food research 20180103 2

<h4>Scope</h4>Bovine lactoferrin (bLF) is an ingredient of food supplements and infant formulas given its antimicrobial and antiviral properties. We modified bLF enzymatically to alter its N-glycosylation and to isolate the glycan chains. The aims of this study include (1) to evaluate whether such derivates induce responses via pattern recognition receptors namely Toll-like receptors (TLRs) and (2) to relate those responses to their different glycosylation profiles.<h4>Methods and results</h4>Th ...[more]

PMID: 28971586

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Project description:Toll-like receptor 8 (TLR-8) plays a role in the pathogenesis of autoimmune disorders and associated gastrointestinal symptoms that reduce quality of life of patients. Dietary interventions are becoming more accepted as mean to manage onset, progression, and treatment of a broad spectrum of inflammatory conditions. In this study, we assessed the impact of N-glycans derived from bovine lactoferrin (bLF) on the inhibition of TLR-8 activation. We investigated the effects of N-glycans in their native form, as well as in its partially demannosylated and partially desialylated form, on HEK293 cells expressing TLR-8, and in human monocyte-derived dendritic cells (MoDCs). We found that in HEK293 cells, N-glycans strongly inhibited the ssRNA40 induced TLR-8 activation but to a lesser extent the R848 induced TLR-8 activation. The impact was compared with a pharmaceutical agent, i.e., chloroquine (CQN), that is clinically applied to antagonize endosomal TLR- activation. Inhibitory effects of the N-glycans were not influenced by the partially demannosylated or partially desialylated N-glycans. As the difference in charge of the N-glycans did not influence the inhibition capacity of TLR-8, it is possible that the inhibition mediated by the N-glycans is a result of a direct interaction with the receptor rather than a result of pH changes in the endosome. The inhibition of TLR-8 in MoDCs resulted in a significant decrease of IL-6 when cells were treated with the unmodified (0.5-fold, p < 0.0001), partially demannosylated (0.3-fold, p < 0.0001) and partially desialylated (0.4-fold, p < 0.0001) N-glycans. Furthermore, the partially demannosylated and partially desialylated N-glycans showed stronger inhibition of IL-6 production compared with the native N-glycans. This provides evidence that glycan composition plays a role in the immunomodulatory activity of the isolated N-glycans from bLF on MoDCs. Compared to CQN, the N-glycans are specific inhibitors of TLR-8 activation and of IL-6 production in MoDCs. Our findings demonstrate that isolated N-glycans from bLF have attenuating effects on TLR-8 induced immune activation in HEK293 cells and human MoDCs. The inhibitory capacity of N-glycans isolated from bLF onTLR-8 activation may become a food-based strategy to manage autoimmune, infections or other inflammatory disorders.

Dataset Information

Dietary N-Glycans from Bovine Lactoferrin and TLR Modulation.

Publications

Dietary N-Glycans from Bovine Lactoferrin and TLR Modulation.

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