Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE

Tian, Jane; Avalos, Ana M.; Mao, Su-Yau; Chen, Bin; Senthil, Kannaki; Wu, Herren; Parroche, Peggy; Drabic, Stacey; Golenbock, Douglas T.; Sirois, Cherilyn M.; Hua, Jing; An, Ling; Audoly, Laurent; Rosa, Greg La; Bierhaus, Angelika; Naworth, Peter; Marshak‐Rothstein, Ann; Crow, Mary K.; Fitzgerald, Katherine A.; Latz, Eicke; Kiener, Peter A.; Coyle, Anthony J.

doi:10.1038/ni1457

Cited by 1,232 publications

(1,132 citation statements)

References 63 publications

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“…RAGE in adaptive immune responses HMGB1 interaction with RAGE activates plasmacytoid dendritic cells and B cells in response to DNA-containing immune complexes and thus contributes to autoimmune pathogenesis [74]. Activation of innate immune responses may alter the way in which antigens are presented to T and other cells of the adaptive immune response.…”

Section: The Role Of Rage In Various Pathological Settingsmentioning

confidence: 99%

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

2009

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The pattern recognition receptor or receptor for AGE (RAGE) is constitutionally expressed in a few cell types only. However in almost all cells studied so far it is induced by reactions known to initiate inflammation. Its biological activity seems to be mainly dependent on the presence of its various ligands, including AGE, S100-calcium binding protein/calgranulins, high-mobility group protein 1, amyloid-β-peptides and the family of β-sheet fibrils, all known to be elevated in chronic metabolic, malignant and inflammatory diseases. The RAGE pathway interacts with cytokine-, lipopolysaccharide-, oxidised LDL-and glucose-triggered cellular reactions by turning a short-lasting inflammatory response into a sustained change of cellular function driven by perpetuated activation of the proinflammatory transcription factor, nuclear factor kappa-B. RAGE-mediated persistent cell activation is of pivotal importance in various experimental and clinical settings, including diabetes and its complications, neurodegeneration, ageing, tumour growth, and autoimmune and infectious inflammatory disease. Due to RAGE's central role in maintaining perpetuated cell activation, various therapeutic attempts to block RAGE or its ligands are currently under investigation. Despite broad experimental evidence for the role of RAGE in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE×ligand interaction in chronic diseases.

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Section: The Role Of Rage In Various Pathological Settingsmentioning

confidence: 99%

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

2009

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“…Necrotic cells, especially those derived from cancer tissues, release passivelly HMGB1 protein, which mediates regional inflammation and the development of cancer (Scaffidi et al, 2002;Luo et al, 2012). Extracellular HMGB1 protein interacts with several receptors including the receptors for advanced glycation end products (RAGE), Toll-like receptors (TLR) and CD24 (Tian et al, 2007). It has been reported that HMGB1 and RAGE were overexpressed in ccRCC.…”

Section: Introductionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background:The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.

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“…The change of autoantibody and pro-inflammation cytokine levels in serum and urine, the monocyte chemotactic protein-1 (MCP-1) expression in kidney and the B cell activating factor (BAFF) (11)(12)(13)(14)(15) expression in spleen, all of which may play a role in the development of lupus nephritis, was also determined to explore the mechanism of action of artesunate.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study of the Therapeutic Efficacy and Mechanism of Artesunate in the MRL/lpr Murine Model of Systemic Lupus Erythematosus

Ouyang

Zhang

et al. 2009

Cell Mol Immunol

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Recent evidence indicates that artesunate has immunomodulatory properties that might be useful for treating autoimmune disease. In this study, we conducted a pilot study and explored the effect and mechanism of artesunate on the treatment of systemic lupus erythematosus using an MRL/lpr murine model. MRL/lpr mice were divided into control, cyclophosphamide (CTX) and artesunate treatment groups. Blood was collected to measure serum levels of creatinine, antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody. Twenty-four-hour urine was collected to measure levels of proteinuria. The concentration of monocyte chemotactic protein-1 (MCP-1) in serum and urine was measured. The expression of MCP-1 in kidney was detected by Western blot and immunohistochemistry assay, respectively. The expression of B cell activating factor (BAFF) in spleen was determined by real time-PCR and immunoblotting. We found that artesunate significantly increased the survival rate, body weight and blood leukocyte counts, and reduced the serum levels of ANA and anti-dsDNA antibody titer, 24 h urinary protein, and serum creatinine. Our results indicated that artesunate could decrease MCP-1, major pro-inflammation cytokine, in serum, urine and kidney. We also found that the level of BAFF, the major B cell activation factor, was decreased in artesunate treated MRL/lpr mice. Its efficacy was comparable with that of CTX in this study. Taken

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Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE

Cited by 1,232 publications

References 63 publications

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

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

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

A Pilot Study of the Therapeutic Efficacy and Mechanism of Artesunate in the MRL/lpr Murine Model of Systemic Lupus Erythematosus

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