Structural differences in bacterial lipopolysaccharides determine atherosclerotic plaque progression by regulating the accumulation of neutrophils


      • E. coli lipopolysaccharide (LPS) with a hexa-acylated lipid A moiety strongly induced endotoxemia, but Bacteroides LPS with a penta- or tetra-acylated lipid A did not.
      • Endotoxemia induced by E. coli LPS induced neutrophil accumulation and subsequent neutrophil extracellular traps (NETs) formation and IL-1β production in plaque lesions, leading to exacerbated atherosclerosis, which was not observed with LPS derived from Bacteroides.
      • NETs formation and IL-1β production were also observed by immunohistological assessment of human coronary artery plaques.


      Background and aims

      Gut microbial lipopolysaccharide (LPS) induces endotoxemia, an independent risk factor for cardiovascular disease (CVD). However, no studies have demonstrated how structural differences in each bacterial LPS contribute to endotoxemia. Here, we investigated the effects of different acyl chains in the lipid A moiety of LPS on endotoxemia and the subsequent immune response and atherosclerotic plaque formation.


      Apoe−/− mice were intraperitoneally administered 2 mg/kg of Escherichia coli-derived LPS (E. LPS, as a representative of hexa-acylated lipid A), Bacteroides-derived LPS (B. LPS, as a representative of penta- or tetra-acylated lipid A), or saline (control) once a week, six times. An immunohistological assessment was performed on plaque sections.


      E. LPS administration induced endotoxemia, but B. LPS and saline did not. In E. LPS-treated mice, total plaque areas in the aortic root were significantly increased, and neutrophil accumulation and increased formation of neutrophil extracellular traps (NETs) were observed at the plaque lesions, but not in B. LPS-treated mice. A single dose of E. LPS significantly increased the accumulation of neutrophils in plaque lesions on day 3, and NET formation on day 7. E. LPS also increased interleukin-1 beta (IL-1β) production in plaque lesions on day 7. Furthermore, NET formation and IL-1β production were also observed in human coronary plaques.


      We identified a previously unknown link between structural differences in LPS and atherosclerosis. Lowering microbial LPS activity may reduce NET formation in plaques and prevent CVD progression.

      Graphical abstract


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