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Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.

ABSTRACT: Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the interaction [corrected] of CD24 and SiglecG (SIGLEC10 in human). Here we use an intestinal perforation model of sepsis to show that microbial sialidases target the sialic acid-based recognition of CD24 by SiglecG/10 to exacerbate inflammation. Sialidase inhibitors protect mice against sepsis by a mechanism involving both CD24 and Siglecg, whereas mutation of either gene exacerbates sepsis. Analysis of sialidase-deficient bacterial mutants confirms the key contribution of disrupting sialic acid-based pattern recognition to microbial virulence and supports the clinical potential of sialidase inhibition for dampening inflammation caused by infection.

SUBMITTER: Chen GY

PROVIDER: S-EPMC4090080 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.

Chen Guo-Yun GY Chen Xi X King Samantha S Cavassani Karen A KA Cheng Jiansong J Zheng Xincheng X Cao Hongzhi H Yu Hai H Qu Jingyao J Fang Dexing D Wu Wei W Bai Xue-Feng XF Liu Jin-Qing JQ Woodiga Shireen A SA Chen Chong C Sun Lei L Hogaboam Cory M CM Kunkel Steven L SL Zheng Pan P Liu Yang Y

Nature biotechnology 20110410 5

Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the interaction [corrected] of CD24 and SiglecG ...[more]

PMID: 21478876

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Project description:BACKGROUND:Sialic acids are widely distributed in animal tissues, and aberrantly expressed in a variety of cancer types. High expression of sialic acid contributes to tumor aggressiveness by promoting cell proliferation, migration, angiogenesis, and metastasis. Sialidases are responsible for removal of sialic acids from glycoproteins and glycolipids. METHODS:N-glycomics of bladder cancer cells were detected by MALDI-TOF mass spectrometry. Sialic acid modification in bladder cancer tissue was determined by lectin blot. The down-regulation of NEU1 in bladder cancer cells was determined by high resolution liquid chromatography mass spectrometry (HR LC-MS). The effects of sialidase NEU1 expression on proliferation and apoptosis of human bladder cancer cells were examined by western blot, RT-PCR, confocal imaging and flow cytometry. Moreover, the function of sialic acids on fibronectin-integrin ?5?1 interaction were assayed by immunoprecipitation and ELISA. The importance of NEU1 in tumor formation in vivo was performed using BALB/c-nu mice. Expression of NEU1 in primary human bladder cancer tissue samples was estimated using bladder cancer tissue microarray. RESULTS:(1) Downregulation of NEU1 was primarily responsible for aberrant expression of sialic acids in bladder cancer cells. (2) Decreased NEU1 expression was correlated with bladder cancer progression. (3) NEU1 overexpression enhanced apoptosis and reduced proliferation of bladder cancer cells. (4) NEU1 disrupted FN-integrin ?5?1 interaction and deactivated the Akt signaling pathway. (5) NEU1 significantly suppressed in vivo tumor formation in BALB/c-nu mice. CONCLUSIONS:Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin ?1 and inhibiting the Akt signaling pathway. Our observations indicate that NEU1 is an important modulator of the malignant properties of bladder cancer cells, and is a potential therapeutic target for prognosis and treatment of bladder cancer. Video Abstract.

Project description:Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model.IMPORTANCE Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases.

Dataset Information

Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.

Publications

Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.

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