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.
Highlights
Despite recent advances in antibiotic therapy and intensive care, sepsis remains a significant problem in critically ill patients with >225,000 victims in the U.S alone
To understand the role of cytokines in sepsis, we characterized the kinetics of circulating high mobility group box 1 (HMGB1) and other cytokines in a group of septic patients admitted to the Emergency Medicine Department at North Shore University Hospital
In 8 of 23 septic patients, serum HMGB1 levels paralleled with the clinical scores; circulating HMGB1 levels returned toward baseline when these patients recovered from septic shock or severe sepsis (Figure 1A, data not shown)
Summary
Despite recent advances in antibiotic therapy and intensive care, sepsis remains a significant problem in critically ill patients with >225,000 victims in the U.S alone. The pathogenesis of sepsis remains poorly understood, but is attributable to dysregulated immune responses orchestrated by innate immune cells including macrophages/monocytes [1]. Upon PRR–PAMP engagement, innate immune cells sequentially release early (for example, tumor necrosis factor [TNF], interleukin [IL]-1, interferon [IFN]-γ and coldinducible RNA-binding protein [CIRP]) [3,4] and late (for example, nitric oxide [NO] or high mobility group box 1 [HMGB1]) proinflammatory mediators [5,6]. In addition to stimulating macrophages/ monocytes to release late proinflammatory mediators, early cytokines alter the expression of liver-derived acutephase proteins that participate in the regulation of inflammatory responses. TNF, IL-1β and interferon (IFN)-γ induce the expression of serum amyloid A (SAA) in hepatocytes [10] and macrophages/monocytes [11], resulting in subsequent SAA secretion upon cleaving off the signal sequence. During endotoxemia, circulating SAA levels are significantly elevated (up to 1,000-fold) within 16–24 h as a result of de novo expression of early cytokine inducers and subse-
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