Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases

Taguchi, Akihiko; Dc, Blood; G, Del Toro; Canet, Amparo; Dc, Lee; Qu, Wei; Tanji, Nozomu; Lu, Ye; Lalla, Evanthia; Fu, Chunyan; Ma, Hofmann; Kislinger, Thomas; Ingram, Mark; Lü, Aiping; Tanaka, Hiroko; Hori, Osamu; Ogawa, Satoshi; Dm, Stern; Schmidt, Annemarie

doi:10.1038/35012626

Cited by 1,123 publications

(1,124 citation statements)

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“…4). A similar role for RAGE in mediating HMGB1 functional activities has been demonstrated in different models, including regeneration of peripheral nerves [38,62] and tumor growth/metastasis [63].…”

Section: Discussionsupporting

confidence: 56%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the bestcharacterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. IntroductionDendritic cells (DC) are potent antigen-presenting cells bridging the innate and adaptive immune responses. To date, two subsets of DC have been identified in humans: myeloid DC and plasmacytoid DC (PDC), the latter also referred to as type I interferon (IFN-a)-producing cells [1][2][3][4][5][6]. PDC recognize viral or bacterial DNA patterns, consisting of unmethylated CpG motifs in the context of species-dependent surrounding sequences (CpG) [7]. As a consequence they produce, within a few hours, large amounts of . Based on their ability to induce IFN-a secretion by PDC, two types of CpG have been described: CpG 2216 (CpG-A), which induces high amounts of IFN-a, and CpG 2006 (CpG-B), which promotes survival, maturation and migration of PDC to the lymph nodes, but induces lower amounts of . PDC sustain the priming of naive T cells and their differentiation into Th1/Th2 effectors [15][16][17] or into regulatory T cells [16,[18][19][20][21][22].Recent studies shed light on the events involved in the recognition of microbial DNA by human PDC, the only subset of human DC that expresses the Toll-like receptor 9 (TLR9) [12]. Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24]. TLR9 activation leads to recruitment of the MyD88 adaptor protein and phosphorylation of the IL-1R-associated kinase (IRAK). Phosphorylated IRAK associates with the adaptor molecule TNF-associated factor 6 (TRAF6) [25]. Two separate signaling pathways, JNK and NF-jB, are then activated, promoting PDC maturation and survival. IFN-a induction, an event exclusively occurring in PDC, depends on the formation of a complex consisting of MyD88, TRAF6 and the IRF7 transcription factor, as well as on TRAF6-dependent ubiquitination [26].The events that determine the outcome of the interaction of PDC with T cells, and in particular the induction of effector or regulatory immune responses, are poorly characterized. Environmental signals that Here we report that HMGB1 is exported from the nucleus of PDC upon selective engagement of TLR9 an...

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Section: Discussionsupporting

confidence: 56%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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“…We and others have shown that ERK activity increases as early as 0.5 to 1 h after ischemia in the middle cerebral artery territory (Alessandrini et al, 1999;Wu et al, 2000). This signaling is potentially linked to TLR2, TLR4, and/or RAGE activation (Ishihara et al, 2003;Park et al, 2003;Taguchi et al, 2000) and is known to promote transcription of cytokines such as TNFa (Fiuza et al, 2003). Tumor necrosis factor a mRNA reportedly increases within 1 h after induction of ischemia in the periinfarct and infarct area, peaks at 12 h, and remains elevated for up to 24 h (Gregersen et al, 2000;Lambertsen et al, 2002Lambertsen et al, , 2005Schroeter et al, 2003;Yang et al, 1999).…”

Section: Discussionmentioning

confidence: 86%

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

366

299

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The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

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“…Membrane-associated HMGB-1 mediates cellular proliferation and growth by signaling through the receptor for advanced glycation end products (RAGE) (13). Interaction of HMGB-1 with RAGE activates intracellular signal transduction through mechanisms involving nuclear factor B (NF-B), mitogen-activated protein (MAP) kinases, plasminogen activation, Cdc42, and Rac (11,13).…”

Section: Hmgb-1 As a Nuclear Dna Binding Protein And Membrane-associamentioning

confidence: 99%

High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis

Ulloa¹,

Batliwalla²,

Andersson³

et al. 2003

Arthritis & Rheumatism

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Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases

Cited by 1,123 publications

References 24 publications

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis

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