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Molecular Medicine

, Volume 21, Issue 1, pp 515–525 | Cite as

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

  • Wei Li
  • Shu Zhu
  • Jianhua Li
  • Jason D’Amore
  • John D’Angelo
  • Huan Yang
  • Ping Wang
  • Kevin J. Tracey
  • Haichao Wang
Research Article

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.

Notes

Acknowledgments

The authors thank Dr. Maria de Beer for providing the SAA1/SAA2 KO mice. This work was supported by the National Institute of General Medical Sciences (NIGMS, R01GM063075) and the National Center of Complementary and Alternative Medicine (NCCAM, R01AT05076).

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Authors and Affiliations

  • Wei Li
    • 1
    • 2
  • Shu Zhu
    • 1
    • 2
  • Jianhua Li
    • 2
  • Jason D’Amore
    • 1
  • John D’Angelo
    • 1
  • Huan Yang
    • 2
  • Ping Wang
    • 2
  • Kevin J. Tracey
    • 2
  • Haichao Wang
    • 1
    • 2
  1. 1.Department of Emergency MedicineNorth Shore University HospitalManhassetUSA
  2. 2.The Feinstein Institute for Medical ResearchManhassetUSA

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