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
View: Text | PDF
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

×

Figure 4

The 3′SL inflammation response is associated with LXR and SREBP signal–dependent transcription factors.

Options: View larger image (or click on image) Download as PowerPoint
The 3′SL inflammation response is associated with LXR and SREBP signal–d...
(A) Scatter plot depicting the enhancers as defined by H3K27ac in their relationship to LPS stimulation with and without 3′SL coincubation. (B) Venn-diagram of global enhancers affected by 3′SL and LPS compared with LPS induced enhancers. (C) Venn-diagram of 3′SL-LPS–induced genes compared with LPS-induced enhancers associated with LXR/SREBP-bound loci. (D) De novo motif analysis of 3′SL-LPS–induced enhancers (versus LPS) using a GC-matched genomic background. (E) Heatmap of the fold change in 3′SL upregulated H3K27ac levels at ATAC-Seq–defined gene loci that demonstrated binding for LXR or SREBP. (F) Distribution of H3K27Ac tag densities, in the vicinity of genomic regions cobound by LXR, SREBP, or PU.1, in BMDMs treated with indicated stimuli for 6 hours. (G) Distribution of p300 tag densities, in the vicinity of genomic regions cobound by LXR, SREBP, or PU.1, in BMDMs treated with indicated stimuli for 6 hours. (H) UCSC genome browser images illustrating normalized tag counts for H3K27ac at Stard4 and Scd2 target loci together with mapped LXR and SREBP binding sites. (I–L) Relative mRNA levels of target genes in BMDMs transfected with nontargeting control siRNA (siScr) or siScap or BMDMs isolated from Lxrα/β-KO mice (Lxr–/–) stimulated with PBS and LPS ± 3′SL. (n = 4 silencing experiments, Lxr–/– BMDMs from 3 individual mice). Two-way ANOVA with Fisher’s LSD test. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent mean ± SEM.