Serum amyloid A promotes LPS clearance and suppresses LPS-induced inflammation and tissue injury

EMBO Rep. 2018 Oct;19(10):e45517. doi: 10.15252/embr.201745517. Epub 2018 Aug 20.

Abstract

Lipopolysaccharide (LPS) is a major microbial mediator for tissue injury and sepsis resulting from Gram-negative bacterial infection. LPS is an external factor that induces robust expression of serum amyloid A (SAA), a major constituent of the acute-phase proteins, but the relationship between SAA expression and LPS-induced tissue injury remains unclear. Here, we report that mice with inducible transgenic expression of human SAA1 are partially protected against inflammatory response and lung injury caused by LPS and cecal ligation and puncture (CLP). In comparison, transgenic SAA1 does not attenuate TNFα-induced lung inflammation and injury. The SAA1 expression level correlates inversely with the endotoxin concentrations in serum and lung tissues since SAA1 binds directly to LPS to form a complex that promotes LPS uptake by macrophages. Disruption of the SAA1-LPS interaction with a SAA1-derived peptide partially reduces the protective effect and exacerbates inflammation. These findings demonstrate that acute-phase SAA provides innate feedback protection against LPS-induced inflammation and tissue injury.

Keywords: acute‐phase response; inflammation; innate immunity; lipopolysaccharide; serum amyloid A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Gene Expression Regulation / immunology
  • Gram-Negative Bacteria / chemistry
  • Gram-Negative Bacteria / pathogenicity
  • Gram-Negative Bacterial Infections / genetics*
  • Gram-Negative Bacterial Infections / immunology
  • Gram-Negative Bacterial Infections / microbiology
  • Humans
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Inflammation / genetics*
  • Inflammation / immunology
  • Inflammation / microbiology
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / pharmacology
  • Lung Injury / genetics*
  • Lung Injury / microbiology
  • Lung Injury / pathology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Transgenic
  • Sepsis / genetics*
  • Sepsis / immunology
  • Sepsis / microbiology
  • Serum Amyloid A Protein / genetics*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Lipopolysaccharides
  • SAA1 protein, human
  • Serum Amyloid A Protein
  • Tumor Necrosis Factor-alpha