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  • 1
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    PALLD Regulates Phagocytosis by Enabling Timely Actin Polymerization and Depolymerization [INNATE IMMUNITY AND INFLAMMATION] (2017)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2017-08-22
    Description: PALLD is an actin cross-linker supporting cellular mechanical tension. However, its involvement in the regulation of phagocytosis, a cellular activity essential for innate immunity and physiological tissue turnover, is unclear. We report that PALLD is highly induced along with all- trans -retinoic acid–induced maturation of myeloid leukemia cells, to promote Ig- or complement-opsonized phagocytosis. PALLD mechanistically facilitates phagocytic receptor clustering by regulating actin polymerization and c-Src dynamic activation during particle binding and early phagosome formation. PALLD is also required at the nascent phagosome to recruit phosphatase oculocerebrorenal syndrome of Lowe, which regulates phosphatidylinositol-4,5-bisphosphate hydrolysis and actin depolymerization to complete phagosome closure. Collectively, our results show a new function for PALLD as a crucial regulator of the early phase of phagocytosis by elaborating dynamic actin polymerization and depolymerization.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 2
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    LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription in Macrophages through Modulating SWI/SNF-Mediated Chromatin Remodeling [INNATE IMMUNITY AND INFLAMMATION] (2016)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2016-03-05
    Description: Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (〉200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in macrophages upon TLR ligation is lincRNA-Cox2, which was recently shown to mediate the activation and repression of distinct classes of immune genes in innate immune cells. We report that lincRNA-Cox2 , located at chromosome 1 proximal to the PG-endoperoxide synthase 2 ( Ptgs2/Cox2 ) gene, is an early-primary inflammatory gene controlled by NF-B signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-B–regulated late-primary inflammatory response genes stimulated by bacterial LPS. Specifically, lincRNA-Cox2 is assembled into the switch/sucrose nonfermentable (SWI/SNF) complex in cells after LPS stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-B subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory-response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role for NF-B–induced lincRNA-Cox2 as a coactivator of NF-B for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 3
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    Transcription Factor Repertoire of Homeostatic Eosinophilopoiesis [IMMUNE SYSTEM DEVELOPMENT] (2015)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2015-09-05
    Description: The production of mature eosinophils (Eos) is a tightly orchestrated process with the aim to sustain normal Eos levels in tissues while also maintaining low numbers of these complex and sensitive cells in the blood. To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identify genome-wide transcriptome and epigenome changes that occur during homeostasis at critical developmental stages, including Eos-lineage commitment and lineage maturation. Our analyses revealed a markedly greater number of transcriptome alterations associated with Eos maturation (1199 genes) than with Eos-lineage commitment (490 genes), highlighting the greater transcriptional investment necessary for differentiation. Eos-lineage–committed progenitors (EoPs) were noted to express high levels of granule proteins and contain granules with an ultrastructure distinct from that of mature resting Eos. Our analyses also delineated a 976-gene Eos-lineage transcriptome that included a repertoire of 56 transcription factors, many of which have never previously been associated with Eos. EoPs and Eos, but not granulocyte-monocyte progenitors or neutrophils, expressed Helios and Aiolos, members of the Ikaros family of transcription factors, which regulate gene expression via modulation of chromatin structure and DNA accessibility. Epigenetic studies revealed a distinct distribution of active chromatin marks between genes induced with lineage commitment and genes induced with cell maturation during Eos development. In addition, Aiolos and Helios binding sites were significantly enriched in genes expressed by EoPs and Eos with active chromatin, highlighting a potential novel role for Helios and Aiolos in regulating gene expression during Eos development.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 4
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    {alpha}3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells [IMMUNOGENETICS] (2017)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2017-09-06
    Description: Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4 . HLA-A11svE4 is located on the cell surface without β2-microglobulin (β2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with β2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with β2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8 + T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 5
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    Deep Coverage Tissue and Cellular Proteomics Revealed IL-1{beta} Can Independently Induce the Secretion of TNF-Associated Proteins from Human Synoviocytes [SYSTEMS IMMUNOLOGY] (2018)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2018-01-09
    Description: Synovitis is a key contributor to the inflammatory environment in osteoarthritis (OA) joints. Currently, the biological therapy of OA is not satisfactory in multiple single-target trials on anti-TNF agents, or IL-1 antagonists. Systems biological understanding of the phosphorylation state in OA synovium is warranted to direct further therapeutic strategies. Therefore, in this study, we compared the human synovial phosphoproteome of the OA with the acute joint fracture subjects. We found that OA synovium had significantly more phosphoproteins, and 82 phosphoproteins could only be specifically found in all the OA samples. Differentially expressed proteins of the OA synovium were focusing on endoplasmic reticulum–/Golgi-associated secretion and negative regulation of cell proliferation, which was verified through an IL-1β–treated human synoviocyte (HS) in vitro model. With data-independent acquisition–based mass spectrometry, we found that IL-1β could induce HS to secrete proteins that were significantly associated with the endosomal/vacuolar pathway, endoplasmic reticulum/Golgi secretion, complement activation, and collagen degradation. Especially, we found that while specifically suppressing HS endocytosis, IL-1β could activate the secretion of 25 TNF-associated proteins, and the change of SERPINE2 and COL3A1 secretion was verified by immunoblotting. In conclusion, our results suggest that OA synovium has a polarized phosphoproteome to inhibit proliferation and maintain active secretion of HS, whereas IL-1β alone can transform HS to produce a synovitis-associated secretome, containing numerous TNF-associated secretory proteins in a TNF-independent mode.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 6
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    The NF-{kappa}B-Responsive Long Noncoding RNA FIRRE Regulates Posttranscriptional Regulation of Inflammatory Gene Expression through Interacting with hnRNPU [INNATE IMMUNITY AND INFLAMMATION] (2017)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2017-11-07
    Description: Long noncoding RNAs, a newly identified class of noncoding RNAs, are important regulators of gene expression in innate immunity. We report in this study that the transcription of FIRRE, a conserved long noncoding RNA between humans and mice, is controlled by NF-B signaling in macrophages and intestinal epithelial cells. Functionally, FIRRE appears to positively regulate the expression of several inflammatory genes in macrophages or intestinal epithelial cells in response to LPS stimulation via posttranscriptional mechanisms. Specifically, FIRRE physically interacts with heterogeneous nuclear ribonucleoproteins U, regulating the stability of mRNAs of selected inflammatory genes through targeting the AU-rich elements of their mRNAs in cells following LPS stimulation. Therefore, our data indicate a new regulatory role for NF-B–responsive FIRRE in the posttranscriptional regulation of inflammatory genes in the innate immune system.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 7
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    IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis [INNATE IMMUNITY AND INFLAMMATION] (2017)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2017-11-21
    Description: This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling in mice attenuated tissue repair of dextran sulfate sodium (DSS)-induced damage in colon epithelium and markedly reduced tumor development in an azoxymethane/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing), was highly induced in DSS-treated colon tissues and tumors in an IL-17RC–dependent manner. PLET1 expression was induced in LGR5 + colon epithelial cells after DSS treatment. LGR5 + PLET1 + marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in an azoxymethane/DSS model of colitis-associated cancer. Our results suggest that IL-17A–induced PLET1 expression contributes to tissue repair and colon tumorigenesis.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 8
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    CEP78 is mutated in a distinct type of Usher syndrome (2017)
    BMJ Publishing Group
    Details
    Publication Date: 2017-02-19
    Description: Background Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20–30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. Methods Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. Results Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone–rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78 . RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. Conclusions Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells.
    Keywords: Eye Diseases, Hereditary eye disease, Genetic screening / counselling
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 9
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    BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis (2017)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2017-04-08
    Description: Objective Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. Design We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves –/– and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. Results BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves –/– mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves –/– tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. Conclusion Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 10
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    Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs (2017)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2017-04-08
    Description: Objective Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells’ activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application. Design We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells’ activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3 x 10 6 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry. Results All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived 〉14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ~4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs’ cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models. Conclusions Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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