Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1)

Abstract

Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.

Endothelial cell-expressed Tim-3 facilitates metastasis of melanoma cells by activating the NF-κB pathway

“…Higher HMGB1 levels have been found in tumors with greater metastatic potential (25). Except for inducing Tim-3 expression in endothelial cells as shown in this study, HMGB1 also up-regulates the expression of Eselectin in endothelial cells (4,25). E-selectin modulates transmigration of tumor cells by enhancing transendothelial permeability and migration of tumor cells (26)(27)(28).…”

“…Importantly, endothelial cells also contribute to tumor inflammation and metastasis (1)(2)(3). TLR4 expressed in endothelial cells can be activated by engaging with TLR4 ligands such as LPS or high mobility group box 1 (HMGB1) (4,5). Subsequently, various inflammatory factors are induced in endothelial cells (5)(6)(7).…”

Inflammation and Genetics of Inflammation in Cardiovascular Diseases

“…In return, HMGB1 triggers the expression of other proinflammatory cytokines and reinforces this way the proinflammatory process (Andersson et al, 2000;Wang et al, 1999). Endothelial cells express HMGB1, as well as its receptors RAGE, TLR2 and TLR4 and signalling through theses receptors leads to activation of NFkappaB, which can subsequently induce the expression of HMGB1 receptors (van Beijnum et al, 2008) These studies suggest that HMGB1 may be a critical proinflammatory cytokine and may play an important role in the pathogenesis of CAD. Hu et al (2009) has found markedly increased level of serum HMGB1 that correlated with severity of coronary artery stenosis in patients with stable (SAP) and unstable angina pectoris (USAP), especially in SAP patients.…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…der Redox-Zustand von HMGB1 der Schl ü ssel zum Verst ä ndnis der gegens ä tzlichen Funktionen sein. [106] . Beim oralen Plattenepithelkarzinom fand sich zudem eine Korrelation von RAGE-und VEGF-Werten [107] .…”