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1. chinaXiv:201605.01434 [pdf]

SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7

Guo, Hao; Zhang, Jialong; Zhang, Xuyuan; Wang, Yanbing; Yu, Haisheng; Yin, Xiangyun; Li, Jingyun; Du, Peishuang; Chen, Jianzhu; Su, Lishan; Liu, Yongjun; Zhang, Liguo; Guo, Hao; Zhang, Xuyuan; Yu, Haisheng; Yin, Xiangyun; Li, Jingyun; Plumas, Joel; Chaperot, Laurence; Chen, Jianzhu
Subjects: Biology >> Biophysics >> Immunology

Scavenger receptor class B, member 2 (SCARB2) is essential for endosome biogenesis and reorganization and serves as a receptor for both beta-glucocerebrosidase and enterovirus 71. However, little is known about its function in innate immune cells. In this study, we show that, among human peripheral blood cells, SCARB2 is most highly expressed in plasmacytoid dendritic cells (pDCs), and its expression is further upregulated by CpG oligodeoxynucleotide stimulation. Knockdown of SCARB2 in pDC cell line GEN2.2 dramatically reduces CpG-induced type I IFN production. Detailed studies reveal that SCARB2 localizes in late endosome/lysosome of pDCs, and knockdown of SCARB2 does not affect CpG oligodeoxynucleotide uptake but results in the retention of TLR9 in the endoplasmic reticulum and an impaired nuclear translocation of IFN regulatory factor 7. The IFN-I production by TLR7 ligand stimulation is also impaired by SCARB2 knockdown. However, SCARB2 is not essential for influenza virus or HSV-induced IFN-I production. These findings suggest that SCARB2 regulates TLR9-dependent IFN-I production of pDCs by mediating endosomal translocation of TLR9 and nuclear translocation of IFN regulatory factor 7.

submitted time 2016-05-12 Hits2195Downloads1139 Comment 0

2. chinaXiv:201605.01402 [pdf]

PGE2 Elevates IL-23 Production in Human Dendritic Cells via a cAMP Dependent Pathway

Shi, Quanxing; Yin, Zhao; Zhao, Bei; Sun, Fei; Wang, Shouli; Yu, Haisheng; Yin, Xiangyun; Zhang, Liguo
Subjects: Biology >> Biophysics >> Cell Biology

PGE2 elevates IL-23 production in mouse dendritic cells while inhibits IL-23 production in isolated human monocytes. Whether this differential effect of PGE2 on IL-23 production is cell-type-or species-specific has not been investigated in detail. The present study was designed to investigate the effect of PGE2 on IL-23 production in human DCs and the possible underlying mechanisms. Human monocytes derived dendritic cells (Mo-DCs) were pretreated with or without PGE2. Then the cells were incubated with zymosan. Our results demonstrated that PGE2 promoted zymosan-induced IL-23 production in a concentration dependent manner. In addition, it was found that PGE2 is also able to elevate MyD88-mediated IL-23 p19 promoter activity. More importantly, ELISA data demonstrated that db-cAMP, a cAMP analog, and forskolin, an adenylate cyclase activator, can mimic the effect of PGE2 on zymosan-induced IL-23 production, and rp-cAMP, a protein kinase A (PKA) inhibitor, can block the effect of PGE2. Moreover, PGE2 can increase zymosan-induced expression of the mRNA levels of both p19 and p40 subunits, which was mimicked by db-cAMP and forskolin. Our data suggest that PGE2 elevates the production of IL-23 in humanMo-DCs via a cAMP dependent pathway.

submitted time 2016-05-12 Hits1228Downloads658 Comment 0

3. chinaXiv:201605.01339 [pdf]

Adeno-Associated Virus Vector Mediated Delivery of the HBV Genome Induces Chronic Hepatitis B Virus Infection and Liver Fibrosis in Mice

Ye, Lei; Li, Wuping; Liu, Zhong; Ye, Lei; Li, Wuping; Liu, Zhong; Yu, Haisheng; Zhang, Liguo; Li, Chengwen; Hirsch, Matthew L.; Samulski, R. Jude; Li, Wuping
Subjects: Biology >> Biophysics

Liver cirrhosis and hepatocellular carcinomas are major health problems of chronic hepatitis B virus (HBV) infection. To date, rare model has reproduced liver fibrosis associated with long-term HBV infection which in turn has hindered both the understanding of HBV biology and the development of new treatment options. Here, using adeno-associated virus serotype 8 (AAV8) mediated delivery of a 1.2-kb HBV genome, we successfully generated a chronic HBV infectious mouse model that presents the associated liver fibrosis observed following human infection. After AAV8/HBV1.2 vector administration, mice demonstrated effective HBV replication and transcription which resulted in HBV antigen expression and viremia over 6 months. Although no obvious acute inflammatory response was noted, these mice still developed chronic liver disease and hepatic fibrogenesis as demonstrated by increased ground glass-like hepatocytes, an increasing trend of collagen deposition and upregulated fibrosis markers, including type I collagen, type III collagen, tissue inhibitor of metalloproteinase (TIMP), and transforming growth factor-beta 1(TGF-beta 1). Taken together, AAV-mediated HBV gene delivery to the mouse liver, induced HBV persistent infection accompanied by liver fibrosis which can serve as a model for investigating the precise mechanisms underlying liver fibrosis following chronic HBV infection as well as for the potential development of novel therapeutics.

submitted time 2016-05-11 Hits935Downloads559 Comment 0

4. chinaXiv:201605.01309 [pdf]

A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2

Mi, Zeyun; Ding, Jiwei; Zhang, Quan; Ma, Ling; Shan, Guangzhi; Li, Xiaoyu; Zhou, Jinming; Cen, Shan; Mi, Zeyun; Ding, Jiwei; Zhang, Quan; Ma, Ling; Shan, Guangzhi; Li, Xiaoyu; Zhou, Jinming; Cen, Shan; Zhao, Jianyuan; Wei, Tao; Liu, Zhenlong; Liang, Chen
Subjects: Biology >> Biophysics

Human BST-2 inhibits HIV-1 replication by tethering nascent virions to the cell surface. HIV-1 codes Vpu that counteracts BST-2 by down-regulating this restriction factor from the cell surface. This important function makes Vpu a potential therapeutic target. Yet, no agents have been reported to block Vpu from antagonizing BST-2. In this study, we report a small molecule compound IMB-LA that abrogates the function of Vpu and thereby strongly suppresses HIV-1 replication by sensitizing the virus to BST-2 restriction. Further studies revealed that IMB-LA specifically inhibits Vpu-mediated degradation of BST-2 and restores the expression of BST-2 at the cell surface. Although IMB-LA does not prevent Vpu from interacting with BST-2 or beta-TrCP2-containing ubiquitin E3 ligase, sorting of BST-2 into lysosomes in Vpu-expressing cells is blocked by IMB-LA. Most importantly, HIV-1 release and infection is inhibited by IMB-LA only in BST-2-expressing cells. In summary, results herein demonstrated that IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu, and impair HIV-1 replication in a BST-2 dependent manner, suggesting the feasibility of utilizing small molecule compounds to disable the antagonist function of Vpu and thereby expose HIV-1 to the restriction by BST-2.

submitted time 2016-05-11 Hits1181Downloads627 Comment 0

5. chinaXiv:201605.01296 [pdf]

Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion

Zhang, Zheng; Zhao, Juanjuan; Wang, Fu-Sheng; Zhang, Zheng; Cheng, Liang; Li, Guangming; Reszka-Blanco, Natalia J.; Sum, Lishan; Zhang, Zheng; Zhao, Juanjuan; Zhang, Liguo; Sum, Lishan; Chen, Weiwei; Nie, Weiming; Wang, Fu-Sheng
Subjects: Biology >> Biophysics

Group 3 innate lymphoid cells (ILC3s) have demonstrated roles in promoting antibacterial immunity, maintaining epithelial barrier function, and supporting tissue repair. ILC3 alterations are associated with chronic inflammation and inflammatory disease; however, the characteristics and relevant regulatory mechanisms of this cell population in HIV-1 infection are poorly understood due in part to a lack of a robust model. Here, we determined that functional human ILC3s develop in lymphoid organs of humanized mice and that persistent HIV-1 infection in this model depletes ILC3s, as observed in chronic HIV-1-infected patients. In HIV-1-infected mice, effective antiretroviral therapy reversed the loss of ILC3s. HIV-1-dependent reduction of ILC3s required plasmacytoid dendritic cells (pDCs), IFN-I, and the CD95/FasL pathway, as targeted depletion or blockade of these prevented HIV-1-induced ILC3 depletion in vivo and in vitro, respectively. Finally, we determined that HIV-1 infection induces CD95 expression on ILC3s via a pDC- and IFN-I-dependent mechanism that sensitizes ILC3s to undergo CD95/FasL-mediated apoptosis. We conclude that chronic HIV-1 infection depletes ILC3s through pDC activation, induction of IFN-I, and CD95-mediated apoptosis.

submitted time 2016-05-11 Hits1130Downloads661 Comment 0

6. chinaXiv:201605.01258 [pdf]

Human BDCA2(+)CD123(+)CD56(+) dendritic cells (DCs) related to blastic plasmacytoid dendritic cell neoplasm represent a unique myeloid DC subset

Yu, Haisheng; Yin, Xiangyun; Zhang, Liguo; Zhang, Peng; Cui, Ya; Jiang, Taijiao; Yu, Haisheng; Zhang, Peng; Yin, Xiangyun; Yin, Zhao; Shi, Quanxing; Wang, Shouli; Liu, Guanyuan; Piccaluga, Pier Paolo
Subjects: Biology >> Biophysics >> Cell Biology

Dendritic cells (DCs) comprise two functionally distinct subsets: plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are specialized in rapid and massive secretion of type I interferon (IFN-I) in response to nucleic acids through Toll like receptor (TLR)-7 or TLR-9. In this report, we characterized a CD56(+) DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56(+) DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56(+) DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naive T cells without prior activation. These data suggest that the CD56(+) DCs represent a novel mDC subset mixed with some pDC features. A CD4(+)CD56(+) hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its expression of characteristic molecules of pDCs. However, we demonstrated that BPDCN is closer to CD56(+) DCs than pDCs by global gene-expression profiling. Thus, we propose that the CD4(+)CD56(+) neoplasm may be a tumor counterpart of CD56(+) mDCs but not pDCs.

submitted time 2016-05-11 Hits1165Downloads646 Comment 0

7. chinaXiv:201605.00718 [pdf]

Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination

Zhu, Danming; Liu, Longchao; Yang, Dan; Bian, Yingjie; Sun, Zhichen; He, Junming; Zhang, Liguo; Peng, Hua; Fu, Yang-Xin; Liu, Longchao; Bian, Yingjie; Sun, Zhichen; Fu, Sherry; Fu, Yang-Xin; Su, Lishan;
Subjects: Biology >> Biophysics >> Immunology

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.

submitted time 2016-05-05 Hits1361Downloads621 Comment 0

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