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A Neoglycoconjugate Containing the Human Milk Sugar LNFPIII Drives Anti-Inflammatory Activation of Antigen Presenting Cells in a CD14 Dependent Pathway
Univ Georgia, Dept Infect Dis, Coll Vet Med, Athens, GA 30602 USA.;Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA..
Univ Georgia, Dept Infect Dis, Coll Vet Med, Athens, GA 30602 USA..
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
Univ Georgia, Dept Infect Dis, Coll Vet Med, Athens, GA 30602 USA..
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2015 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 9, e0137495Article in journal (Refereed) Published
Abstract [en]

The milk pentasaccharide LNFPIII has therapeutic action for metabolic and autoimmune diseases and prolongs transplant survival in mice when presented as a neoglycoconjugate. Within LNFPIII is the Lewis(x) trisaccharide, expressed by many helminth parasites. In humans, LNFPIII is found in human milk and also known as stage-specific embryonic antigen-1. LNFPIII-NGC drives alternative activation of macrophages and dendritic cells via NF kappa B activation in a TLR4 dependent mechanism. However, the connection between LNFPIII-NGC activation of APCs, TLR4 signaling and subsequent MAP kinase signaling leading to anti-inflammatory activation of APCs remains unknown. In this study we determined that the innate receptor CD14 was essential for LNFPIII-NGC induction of both ERK and NFkB activation in APCs. Induction of ERK activation by LNFPIII-NGC was completely dependent on CD14/TLR4-Ras-Raf1/TPL2-MEK axis in bone marrow derived dendritic cells (BMDCs). In addition, LNFPIII-NGC preferentially induced the production of Th2 "favoring" chemokines CCL22 and matrix metalloprotease protein-9 in a CD14 dependent manner in BMDCs. In contrast, LNFPIII-NGC induces significantly lower levels of Th1 "favoring" chemokines, MIP1 alpha, MIP1 beta and MIP-2 compared to levels in LPS stimulated cells. Interestingly, NGC of the identical human milk sugar LNnT, minus the alpha 1-3 linked fucose, failed to activate APCs via TLR4/MD2/CD14 receptor complex, suggesting that the alpha 1-3 linked fucose in LNFPIII and not on LNnT, is required for this process. Using specific chemical inhibitors of the MAPK pathway, we found that LNFPIII-NGC induction of CCL22, MMP9 and IL-10 production was dependent on ERK activation. Over all, this study suggests that LNFPIII-NGC utilizes CD14/TLR4-MAPK (ERK) axis in modulating APC activation to produce anti-inflammatory chemokines and cytokines in a manner distinct from that seen for the pro-inflammatory PAMP LPS. These pathways may explain the in vivo therapeutic effect of LNFPIII-NGC treatment for inflammation based diseases.

Place, publisher, year, edition, pages
2015. Vol. 10, no 9, e0137495
National Category
Organic Chemistry
URN: urn:nbn:se:uu:diva-263433DOI: 10.1371/journal.pone.0137495ISI: 000360688200065PubMedID: 26340260OAI: oai:DiVA.org:uu-263433DiVA: diva2:859554
NIH (National Institute of Health), 5R01AI056484
Available from: 2015-10-07 Created: 2015-09-30 Last updated: 2015-10-07Bibliographically approved

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