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1. chinaXiv:201605.01739 [pdf]

Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages

Xia, Pengyan; Wang, Shuo; Du, Ying; Huang, Guanling; Fan, Zusen; Huang, Guanling; Satoh, Takashi; Akira, Shizuo
Subjects: Biology >> Biophysics >> Immunology

The lineage commitment of HSCs generates balanced myeloid and lymphoid populations in hematopoiesis. However, the underlying mechanisms that control this process remain largely unknown. Here, we show that insulin-insulin receptor (InsR) signaling is required for lineage commitment of multipotent progenitors (MPPs). Deletion of Insr in murine bone marrow causes skewed differentiation of MPPs to myeloid cells. mTOR acts as a downstream effector that modulates MPP differentiation. mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation, which binds to the promoter of Ikaros, leading to its transcription priming. Our findings reveal that the insulin-InsR signaling drives MPP differentiation into lymphoid lineages in early lymphopoiesis, which is essential for maintaining a balanced immune system for an individual organism.

submitted time 2016-05-15 Hits918Downloads463 Comment 0

2. chinaXiv:201605.01527 [pdf]

Deficiency of CD40 Reveals an Important Role for LIGHT in Anti-Leishmania Immunity

Okwor, Ifeoma; Uzonna, Jude E.; Xu, Guilian; Tang, Haidong; Fu, Yang-Xin; Liang, Yong; Uzonna, Jude E.
Subjects: Biology >> Biophysics >> Immunology

We previously showed that LIGHT and its receptor herpes virus entry mediator (HVEM) are important for development of optimal CD4(+) Th1 cell immunity and resistance to primary Leishmania major infection in mice. In this study, we further characterized the contributions of this molecule in dendritic cell (DC) maturation, initiation, and maintenance of primary immunity and secondary anti-Leishmania immunity. Flow-cytometric studies showed that CD8 alpha(+) DC subset was mostly affected by HVEM-Ig and lymphotoxin beta receptor-Ig treatment. LIGHT signaling is required at both the priming and the maintenance stages of primary anti-Leishmania immunity but is completely dispensable during secondary immunity in wild type mice. However, LIGHT blockade led to impaired IL-12 and IFN-gamma responses and loss of resistance in healed CD40-deficient mice after L. major challenge. The protective effect of LIGHT was mediated primarily via its interaction with lymphotoxin beta receptor on CD8 alpha(+) DCs. Collectively, our results show that although LIGHT is critical for maintenance of primary Th1 response, it is dispensable during secondary anti-Leishmania immunity in the presence of functional CD40 signaling as seen in wild type mice.

submitted time 2016-05-12 Hits883Downloads404 Comment 0

3. chinaXiv:201605.01515 [pdf]

Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype

Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Qin, Zhihai; Fu, Yang-Xin; Wang, Shengdian; Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Wang, Yang; Fu, Yang-Xin
Subjects: Biology >> Biophysics >> Immunology

Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.

submitted time 2016-05-12 Hits998Downloads482 Comment 0

4. 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 Hits955Downloads457 Comment 0

5. chinaXiv:201605.01376 [pdf]

The Endoplasmic Reticulum Adaptor Protein ERAdP Initiates NK Cell Activation via the Ubc13-Mediated NF-kappa B Pathway

Chen, Jun; Hao, Lu; Li, Chong; Ye, Buqing; Du, Ying; Zhang, Honglian; Zhu, Pingping; Liu, Benyu; Yang, Liuliu; Fan, Zusen; Chen, Jun; Hao, Lu; Long, Bo; Long, Bo; Li, Peifeng; Tian, Yong
Subjects: Biology >> Biophysics >> Immunology

NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-kappa B pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-kappa B essential modulator ubiquitination to trigger the Ubc13-mediated NF-kappa B pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.

submitted time 2016-05-12 Hits972Downloads474 Comment 0

6. chinaXiv:201605.01374 [pdf]

Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection

Xia, Pengyan; Wang, Shuo; Ye, Buqing; Du, Ying; Huang, Guanling; Zhu, Pingping; Fan, Zusen
Subjects: Biology >> Biophysics >> Immunology

Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high-mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NE-kappa B and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases.

submitted time 2016-05-12 Hits885Downloads440 Comment 0

7. chinaXiv:201605.01367 [pdf]

Commensal bacteria direct selective cargo sorting to promote symbiosis

Zhang, Qin; Pan, Ying; Yan, Ruiqing; Wang, Haifang; Zhang, Xinwen; Liu, Zhihua; Zeng, Benhua; Li, Wenxia; Wei, Hong; Liu, Zhihua
Subjects: Biology >> Biophysics >> Immunology

Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.

submitted time 2016-05-12 Hits851Downloads393 Comment 0

8. chinaXiv:201605.01358 [pdf]

Innate Lymphoid Cells Control Early Colonization Resistance against Intestinal Pathogens through ID2-Dependent Regulation of the Microbiota

Guo, Xiaohuan; Liang, Yong; Zhang, Yuan; Kee, Barbara L.; Fu, Yang-Xin; Guo, Xiaohuan; Liang, Yong; Fu, Yang-Xin; Liang, Yong; Fu, Yang-Xin; Lasorella, Anna; Lasorella, Anna
Subjects: Biology >> Biophysics >> Immunology

Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22.

submitted time 2016-05-11 Hits830Downloads402 Comment 0

9. chinaXiv:201605.01336 [pdf]

Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity

Yang, Jieling; Shao, Feng; Yang, Jieling; Zhao, Yue; Shao, Feng
Subjects: Biology >> Biophysics >> Immunology

Lipopolysaccharide (LPS) is the major component of Gram-negative bacteria cell wall. In innate immunity, extracellular LPS is recognized by Toll-like receptor 4 to stimulate cytokine transcription. Recent studies suggest a 'non-canonical inflammasome' that senses cytoplasmic LPS and activates caspase-11 in mouse macrophages. Unexpectedly, biochemical studies reveal that caspase-11 and its human orthologs caspase-4/caspase-5 are LPS receptors themselves. Direct LPS binding induces caspase-4/caspase-5/caspase-11 oligomerization and activation, triggering cell pyroptosis and anti-bacterial defenses. Caspase-4/caspase-5/caspase-11 recognition of intracellular LPS requires bacterial escape from the vacuole; this process is promoted by interferon-inducible GTPases-mediated lysis of the bacteria-containing vacuole. Non-canonical activation of these inflammatory caspases by LPS not only represents a new paradigm in innate immunity but also critically determines LPS-induced septic shock in mice.

submitted time 2016-05-11 Hits868Downloads412 Comment 0

10. chinaXiv:201605.01299 [pdf]

Identification of candidate antimicrobial peptides derived from abalone hemocyanin

Zhuang, Jun; Wu, Zujian; Xie, Lianhui; Zhuang, Jun; Wu, Zujian; Xie, Lianhui; Coates, Christopher J.; Zhu, Hongtao; Zhu, Ping; Zhu, Hongtao
Subjects: Biology >> Biophysics >> Immunology

Hemocyanins present in invertebrate hemolymph are multifunctional proteins, responsible for oxygen transport and contributing to innate immunity through phenoloxidase-like activity. In arthropods, hemocyanin has been identified as a source of broad-spectrum antimicrobial peptides during infection. Conversely, no hemocyanin-derived antimicrobial peptides have been reported for molluscs. The present study describes a putative antimicrobial region, termed haliotisin, located within the linking sequence between the alpha-helical domain and beta-sheet domain of abalone (Haliotis tuberculata) hemocyanin functional unit E. A series of synthetic peptides based on overlapping fragments of the haliotisin region were tested for their bactericidal potential. Incubating Gram-positive and Gram-negative bacteria in the presence of certain haliotisin peptides, notably peptides 3-4-5 (DTFDYKKFGYRYDSLELEGRS ISRIDELIQQRQEKDRTFAGFLLKGFGTSAS) led to reductions in microbial growth. Furthermore, transmission electron micrographs of haliotisin-treated bacteria revealed damages to the microbial cell wall. Data discussed here provides the first evidence to suggest that molluscan hemocyanin may act as a source of anti-infective peptides. (C) 2014 Elsevier Ltd. All rights reserved.

submitted time 2016-05-11 Hits946Downloads460 Comment 0

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