Serum amyloid A promotes LPS clearance and attenuates LPS-induced tissue injury

Abstract

Abstract Lipopolysaccharide (LPS) is a major microbial mediator of inflammation and is responsible for sepsis resulting from Gram-negative bacterial infections. LPS is an external factor that induces robust expression of serum amyloid A (SAA), a major constituent of the acute-phase proteins in vertebrates, but the relationship between SAA expression and LPS-induced tissue inflammation and injury remains unclear. We constructed transgenic mice expressing human SAA1 under an inducible promoter. These mice were partially protected against lung inflammatory response caused by systemic LPS administration and by cecal ligation and puncture (CLP). Interestingly, transgenic SAA1 expression did not attenuate TNFα-induced lung inflammation and injury. Further experiments identified SAA1 binding to LPS to form a complex that promoted LPS uptake and clearance by macrophages. This effect could be disrupted by a peptide derived from SAA1, and blockade of SAA1-LPS interaction markedly reduced the protective effect of SAA1 and exacerbated inflammation in both the transgenic mice and wildtype mice treated with LPS or CLP. These findings demonstrate that acute-phase SAA expression provides innate protection against LPS-induced inflammation and tissue injury in mice.