Role of Toll-Like Receptors 2 and 4, and the Receptor for Advanced Glycation End Products in High-Mobility Group Box 1-Induced Inflammation in Vivo

Abstract

High-mobility group box 1 (HMGB-1) has been reported as a “late” proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2, TLR-4, and the receptor for advanced glycation end products (RAGE). The objective of this study was to investigate the role of these receptors in the in vivo response to HMGB-1. Therefore, we first performed a time-series experiment with wild-type (Wt) mice. High-mobility group box 1 induced time-dependent elevations of TNF-α, IL-6, monocyte chemoattractant protein 1, and thrombin-antithrombin complex levels in peritoneal lavage fluid and plasma. This inflammatory reaction was accompanied by a prominent and sustained rise in neutrophil counts in the peritoneal cavity. We next administered HMGB-1 to Wt, TLR-2−/−, TLR-4−/−, and RAGE−/− mice. All genotypes showed similar plasma levels of TNF-α, IL-6, IL-10, and thrombin-antithrombin complex at 2 h after intraperitoneal injection of HMGB-1. Compared with Wt mice, both TLR-4−/− and RAGE−/− mice displayed lower TNF-α and IL-6 concentrations and lower neutrophil numbers in their peritoneal lavage fluid. In contrast, TLR-2−/− mice showed increased levels of TNF-α and IL-6 in their peritoneal cavity relative to Wt mice. These data indicate that HMGB-1 induces release of cytokines, activation of coagulation, and neutrophil recruitment in vivo via a mechanism that at least in part depends on TLR-4 and RAGE.

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

“…In chronic kidney disease, serum HMGB-1 levels positively correlated with TNF-α, IL-1β, and IL-6 [43]. Consistent with this, HMGB-1 induced time-dependent elevation of TNF-α, IL-1β, and IL-6 in mice [44]. In contrast, serum…”

Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline

“…Because the Tlr4 −/− mice were not protected in any way from surgery-induced inflammation or POCD, it appears that TLR4 has redundant role in this disease pathway. DAMPs, such as HMGB-1, are recognized by multiple receptors (e.g., RAGE, as well as Tlr4 and Tlr2) and one of the other receptors might be able to induce signaling in the absence of the other (43). Administration of anti-TNF to MyD88 −/− or Tlr4 −/− completely abrogated the surgery-induced IL-1β response and downstream IL-6 production, suggesting a perpetuating role for both these cytokines in the inflammatory response and, possibly, synergism with one another.…”

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…The finding that Rage −/− mice were capable of evoking a normal adaptive immune response contrasted with the efficacy with which sRAGE suppressed inflammation in Rage −/− and wild-type mice. The explanation is that sRAGE functions as a decoy, which prevents RAGE ligands from sequestering to other surface receptors such as the toll-like receptors 2 and 4, CD36, α7-nicotinic acetylcholine receptors and proteoglycans, all of which have been shown to bind to various RAGE ligands [8,15,[76][77][78].…”