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

26052716

DOI

10.2119/molmed.2015.00109


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