The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice
Ariane R. Pessentheiner, Nathanael J. Spann, Chloe A. Autran, Tae Gyu Oh, Kaare V. Grunddal, Joanna K.C. Coker, Chelsea D. Painter, Bastian Ramms, Austin W.T. Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M. Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno P.J. de Winther, Hal M. Hoffman, Martin Philpott, Adam P. Cribbs, Udo Oppermann, Nathan E. Lewis, Joseph L. Witztum, Ruth Yu, Annette R. Atkins, Michael Downes, Ron M. Evans, Christopher K. Glass, Lars Bode, Philip L.S.M. Gordts
Ariane R. Pessentheiner, Nathanael J. Spann, Chloe A. Autran, Tae Gyu Oh, Kaare V. Grunddal, Joanna K.C. Coker, Chelsea D. Painter, Bastian Ramms, Austin W.T. Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M. Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno P.J. de Winther, Hal M. Hoffman, Martin Philpott, Adam P. Cribbs, Udo Oppermann, Nathan E. Lewis, Joseph L. Witztum, Ruth Yu, Annette R. Atkins, Michael Downes, Ron M. Evans, Christopher K. Glass, Lars Bode, Philip L.S.M. Gordts
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Research Article Cell biology Inflammation

The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice

Abstract

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3′sialyllactose (3′SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3′SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3′SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. and oral administration of 3′SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3′SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Authors

Ariane R. Pessentheiner, Nathanael J. Spann, Chloe A. Autran, Tae Gyu Oh, Kaare V. Grunddal, Joanna K.C. Coker, Chelsea D. Painter, Bastian Ramms, Austin W.T. Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M. Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno P.J. de Winther, Hal M. Hoffman, Martin Philpott, Adam P. Cribbs, Udo Oppermann, Nathan E. Lewis, Joseph L. Witztum, Ruth Yu, Annette R. Atkins, Michael Downes, Ron M. Evans, Christopher K. Glass, Lars Bode, Philip L.S.M. Gordts

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Figure 1

HMOs, particularly 3′SL, reduce inflammatory cytokine expression in LPS-activated murine macrophages and human monocytes.

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HMOs, particularly 3′SL, reduce inflammatory cytokine expression in LPS-...
(A and B) Relative mRNA levels of Il6 and Il1b (A), and Il10 and Tnf (B) in Raw264.7 cells with LPS ± pooled HMO (pHMO) incubation (n = 2). (C) IL-6 protein release 6 and 24 hours after LPS ± pHMO incubation (n = 3). (D) Depiction of individually used HMOs. (E and F) Relative mRNA levels of Il6 and Il1b in Raw 264.7 (E) and murine bone marrow–derived macrophages (BMDMs) (F) when treated with individual HMOs (n = 2). (G) Dose-response curve of 3′SL in BMDMs (n = 3). (H) Relative mRNA levels of Il6, Il1b, and Tnf expression in PBS, 3′SL, or LPS ± 3′SL (100 μg/mL) treatment (n = 3–4). (I) IL-1β protein release for 24 hours in BMDMs after LPS+ATP coincubation ± 3′SL (n ≥ 5). (J) Cytokine concentrations in the conditioned medium of BMDMs with 24 hours of LPS ± 3′SL incubation (n = 4). (K) Relative mRNA levels of IL6 and IL1b in LPS-activated human THP-1 cells treated ± 3′SL (n = 3). (L) IL-1β protein release 24 hours after LPS+ATP coincubation ± 3′SL (100 μg/mL) in human peripheral blood monocytes (hPBMCs) from 3 healthy donors. If not otherwise stated, incubations lasted for 6 hours with 10 ng/mL LPS and 100 μg/mL 3′SL or above indicated concentrations of HMOs. Two-way ANOVA with Fisher’s LSD test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Data represented as mean ± SEM.