Publication Date
2015
Journal Title
Mol Med
Abstract
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.
Volume Number
21
Pages
515-25
Document Type
Article
EPub Date
2015/06/09
Status
Faculty, Northwell Researcher
Facility
School of Medicine; Northwell Health
Primary Department
Emergency Medicine
Additional Departments
Molecular Medicine; Surgery; Neurosurgery
PMID
DOI
10.2119/molmed.2015.00109