title: Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors.
abstract: Serum amyloid A (SAA) proteins are known to be 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 for which serum high mobility group box 1 (HMGB1) levels paralleled 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 double-stranded RNA-activated protein kinase R (PKR) expression and HMGB1 release in the wild-type, but not toll-like receptor 4/receptor for advanced glycation end products (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 immunoglobulins G (IgGs) significantly improved animal survival. Collectively, these findings have suggested SAA as an important mediator of inflammatory diseases. Highlights of this study include: human SAA is possibly only expressed in a subset of septic patients; SAA induces HMGB1 release via TLR4 and RAGE receptors; SAA supplementation worsens the outcome of lethal endotoxemia; whereas SAA-neutralizing antibodies confer protection against lethal endotoxemia and sepsis.
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.|The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.|The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: D'Amore
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: D'Angelo
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, United States of America.|The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D000067759:Receptor for Advanced Glycation End Products; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019892:eIF-2 Kinase