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

Yoshizaki, Ayumi; Komura, Kazuhiro; Iwata, Y.; Ogawa, Fumihide; Hara, Toshihide; Muroi, Eiji; Takenaka, Motoi; Shimizu, Kazuhiro; Hasegawa, Minoru; Fujimoto, Manabu; Sato, Shinichi

doi:10.1007/s10875-008-9252-x

Cited by 110 publications

(105 citation statements)

References 55 publications

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“…Innate immune signaling-mediated fibroblast activation was recently reported in SSc and its animal models. In SSc, serum levels and dermal expression levels of endogenous TLR4 ligands, such as HMGB1, hyaluronan, and fibronectin extra domain, are elevated (5,6,8,9). In in vitro experiments, TLR4 signaling induced by these candidate ligands results in fibroblast activation (5,6).…”

Section: Discussionmentioning

confidence: 99%

“…It also was shown that dermal and lung fibrosis is attenuated in bleomycin (BLM)-treated TLR4-deficient mice (7). Endogenous potential TLR4 ligands are up-regulated in SSc lesional skin (5-7), and serum levels correlate with severe organ involvement and immunological abnormalities (8,9). Therefore, the TLR4 signaling pathway is suspected to play a central role in the SSc pathogenesis.…”

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confidence: 99%

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Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally, HMGB1-DNA complexes induce cytokine secretion from mesangial cells in vitro (92). Serum HMGB1 levels are higher in patients with scleroderma and correlate with skin fibrosis and impaired lung function (93). The association with fibrosis is not restricted to autoimmune disorders, given that elevated levels of HMGB1 occur in patients with idiopathic pulmonary fibrosis (IPF) (94).…”

Section: Hmgb1 In Chronic Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

HMGB1 and RAGE in Inflammation and Cancer

Sims¹,

Rowe²,

Rietdijk

et al. 2010

Annu. Rev. Immunol.

1,244

1,096

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The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.

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“…130,131 RAGE is implicated in the development of lung fibrosis 132 and its expression on the fibroblast cell surface has been correlated with SSc severity. 133 TLR4 signaling has been found to induce fibroblast proliferation 134 and the activation of plasmocytoid DCs. 114 Notably, TLR4 inhibition hindered the fibrotic process in a model of LPS-induced lung fibrosis.…”

Section: Systemic Sclerosismentioning

confidence: 99%

Calprotectin in rheumatic diseases

Ometto

Friso

Astorri

et al. 2016

Exp Biol Med (Maywood)

139

105

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Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment. AbstractCalprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-a inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.

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

Cited by 110 publications

References 55 publications

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

HMGB1 and RAGE in Inflammation and Cancer

Calprotectin in rheumatic diseases

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