Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors

Serum amyloid A proteins (SAAs) have been suggested as surrogate markers of sepsis, but their pathogenic roles remain poorly elucidated. Here we provide evidence to support a possible role of SAA as a pathogenic mediator of lethal sepsis. In a subset of septic patients whose serum HMGB1 levels paralleled with the clinical scores, some anti-HMGB1 antibodies detected a 12 kDa protein belonging to the SAA family. In contrast to the most abundant SAA1, human SAA induced PKR expression and HMGB1 release in the wild-type, but not TLR4/RAGE-deficient, macrophages. Pharmacological inhibition of PKR phosphorylation blocked SAA-induced HMGB1 release, suggesting an important role of PKR in SAA-induced HMGB1 release. In animal models of lethal endotoxemia and sepsis, recombinant SAA exacerbated endotoxemic lethality, whereas SAA-neutralizing IgGs significantly improved animal survival. Collectively, these findings have suggested SAA as an important mediator of inflammatory diseases