Apoptotic Cells Induce NF-κB and Inflammasome Negative Signaling
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{"title"=>"Apoptotic cells induce NF-κB and inflammasome negative signaling", "type"=>"journal", "authors"=>[{"first_name"=>"Amir", "last_name"=>"Grau", "scopus_author_id"=>"35975907600"}, {"first_name"=>"Adi", "last_name"=>"Tabib", "scopus_author_id"=>"34870789300"}, {"first_name"=>"Inna", "last_name"=>"Grau", "scopus_author_id"=>"56584049300"}, {"first_name"=>"Inna", "last_name"=>"Reiner", "scopus_author_id"=>"55216783100"}, {"first_name"=>"Dror", "last_name"=>"Mevorach", "scopus_author_id"=>"55403634000"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"603554804", "doi"=>"10.1371/journal.pone.0122440", "pmid"=>"25822487", "issn"=>"19326203", "scopus"=>"2-s2.0-84926500072", "sgr"=>"84926500072"}, "id"=>"3d66bc3d-13ad-386f-8303-a72000d7e965", "abstract"=>"As they undergo phagocytosis, most early apoptotic cells negatively regulate proinflammatory signaling and were suggested as a major mechanism in the resolution of inflammation. The dextran sulfate sodium model is generally viewed as an epithelial damage model suited to investigate innate immune responses. Macrophages primed with LPS and subsequently exposed to DSS secrete high levels of IL-1β in an NLRP3-, ASC-, and caspase-1-dependent manner. The aim of this research was to test the therapeutic effect of a single dose of apoptotic cells in a DSS-colitis model and to explore possible mechanisms. Primary peritoneal macrophages, the DSS mice model, and Nlrp3-deficient mice, were used to assess the effect apoptotic cells on colitis. Immunohistochemistry, flow-cytometer, and western blots helped to explore the effect and mechanisms. Using a variety of NLRP3 triggering mechanisms, we show that apoptotic cells negatively regulate NF-κB and NLRP3 activation in primary peritoneal macrophages, at pre- and post-transcription levels, via inhibition of reactive oxygen species, lysosomal stabilization, and blocking K+ efflux. This property of apoptotic cells is demonstrated in a dramatic clinical, histological, and immunological amelioration of DSS colitis in Balb/c and B6 mice following a single administration of apoptotic cells.", "link"=>"http://www.mendeley.com/research/apoptotic-cells-induce-nf%CE%BAb-inflammasome-negative-signaling", "reader_count"=>13, "reader_count_by_academic_status"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Master"=>2, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Other"=>1}, "reader_count_by_user_role"=>{"Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Master"=>2, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Other"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>5, "Medicine and Dentistry"=>2, "Agricultural and Biological Sciences"=>3, "Immunology and Microbiology"=>2, "Arts and Humanities"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1995451"], "description"=>"<p>IL-1β measured by ELISA (<b>Upper panel</b>) and western blot (<b>Lower panel</b>). IL-1β and caspase-1 were measured in supernatant (SN) and/or intracellular in cell lysate (CL). B6 pMΦ cells were incubated either in the presence of apoptotic cells for 2h followed by LPS priming for 1h (sixth from left, dark bar), or first primed with LPS (to promote NF-κB signaling) for 1h and then incubated with apoptotic cells for 2h (seventh from left, white bar, separated by dashed line). pMΦ were then incubated with various inflammasome inducers. <b>A</b>: nigericin 2.5μM; <b>B</b>: calcium pyrophosphate dihydrate 200μg/mL (CPPD). An anti-mouse actin served as a loading control. Shown are data for A-B, as means ± SEM of 3 independent experiments done in duplicates and WB representative data of three experiments (*<i>p</i><0.001, one way ANOVA).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361261, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g002", "stats"=>{"downloads"=>2, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IL_1_946_inhibition_by_apoptotic_cells_pre_and_post_NF_954_B_triggering_by_LPS_A_B_/1361261", "title"=>"IL-1β inhibition by apoptotic cells pre and post NF-κB triggering by LPS. (A-B).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995459"], "description"=>"<p><b>(A)</b> Upper Panel: <b>I</b>. pMΦ as seen in bright field. <b>II</b>. pMΦ seen by fluorescent microscope following incubation with an ROS-sensitive dye (1μM). <b>III</b>. pMΦ following 3% DSS treatment. Generation of ROS is seen. <b>IV</b>. pMΦ following 3% DSS and apoptotic cell treatment. Inhibition of ROS generation is seen. Original magnification: All panels x100. pMΦ extracted from mice were seeded overnight onto eight-chamber slides at a density of 1x10<sup>5</sup> cells/chamber. After washing, pMΦ were treated for 2h with apoptotic cells followed by treatment with 3% DSS for 30 min. Negative control samples were treated with media only. ROS generation was determined by fluorescence microscopy using a fluorescein fluorescent probe for 30 min with a green filter. The experiments were repeated 3 times, independently; one representative experiment is shown. <b>(B)</b> Flow-cytometer analysis of pMΦ stained with ROS-sensitive dye. ROS generation was determined by flow-cytometer using a fluorescence probe as above, excluding dead cells base on FSC/SSC parameters. Shown are means ± SEM of 3 experiments done in triplicates (*<i>p</i><0.05, one way ANOVA).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361269, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reactive_oxygen_species_ROS_in_pM_934_/1361269", "title"=>"Reactive oxygen species (ROS) in pMΦ.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995458"], "description"=>"<p>Mouse colon tissue sections were stained by immunohistochemistry assay using an antibody against mouse phospho-NF-κB (pNF-κB) p65. After immunostaining, slides were counterstained by hematoxylin. Images show pNF-κB p65 staining. All images are x200. <b>(I)</b> Untreated colon stained with HRP-anti rabbit secondary antibody only, without anti-NF-κB. <b>(II)</b> pNF-κB p65 staining in untreated colon. <b>(III)</b> Large pNF-κB p65 positive stain (black arrow) in 3% DSS-treated colon (3% DSS+PBS). <b>(IV)</b> Fewer pNF-κB p65 positive stain (black arrow) in 3% DSS treated colon with apoptotic cell infusion (3% DSS+ApoCell).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361268, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g005", "stats"=>{"downloads"=>0, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Apoptotic_cell_treatment_inhibits_NF_954_B_in_DSS_induced_colitis_/1361268", "title"=>"Apoptotic cell treatment inhibits NF-κB in DSS-induced colitis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995453"], "description"=>"<p>Balb/c mice were offered distilled water (filled circles), or distilled water with 3% DSS orally ad libitum with treatment of PBS (filled squares) or apoptotic cell (filled triangles). (<b>A</b>) Mean weight of indicated animal number per group (*<i>p</i><0.05, **<i>p</i><0.001, t-test). (<b>B</b>) IBD Clinical Score. Numbers inside boxes indicate the mean score of each parameter with error bar (*<i>p</i><0.001, t-test). Data is presented as mean ± SEM of 3 independent experiments. Weight change, hematochezia and stool consistency were monitored daily. (<b>C</b>) Macroscopic changes of colon and spleen in DSS-treated mice. Photographs of the dissected large intestines and spleens of four mice treated with 3% DSS without- (DSS+PBS) or with apoptotic cell treatment (DSS+ApoCell). <b>(D)</b> IL-1β cytokine level in colonic homogenate from DSS-treated mice. Levels of IL-1β were analyzed by ELISA. Data is presented as mean ± SEM, 3 mice per group (*<i>p</i><0.001, one way ANOVA). <b>(E)</b> IL-1β mRNA levels in colonic homogenate from DSS-treated mice. mRNA was measured by RT-PCR and normalized to untreated colons. Data is presented as mean ± SEM, 4–5 mice per group (*<i>p</i><0.02, t-test)</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361263, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g003", "stats"=>{"downloads"=>4, "page_views"=>187, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Apoptotic_cell_treatment_protects_mice_from_DSS_induced_colitis_/1361263", "title"=>"Apoptotic cell treatment protects mice from DSS-induced colitis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995448"], "description"=>"<p><b>(A)</b> pMΦ from wild type (WT) and NLRP3-deficient mice (<i>Nlrp3</i><sup><i>-/-</i></sup>) and following 4 weeks of cohousing, were treated with 3% DSS in the presence of LPS priming. <b>(B)</b> Influence of apoptotic cell treatment on IL-1β release by pMΦ. Macrophages were treated with apoptotic cells (1:8) prior to LPS and 3% DSS treatment. IL-1β was determined in the supernatant by ELISA. Shown are representative data as means ± SEM of 3-to-5 independent experiments done in triplicate (*<i>p</i><0.01 t-test). <b>(C)</b> The inhibition effect is a direct consequence of apoptotic cell recognition, independent of engulfment. Macrophages were incubated without or with 2 μM cytochalasin D for 45 min before the addition of apoptotic cells and DSS challenge. Shown are representative data as means ± SEM of 2 independent experiments done in triplicate (*p<0.01, one way ANOVA).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361258, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Apoptotic_cells_inhibit_IL_1_946_secretion_and_processing_in_response_to_DSS_is_mediated_by_the_NLRP3_inflammasome_/1361258", "title"=>"Apoptotic cells inhibit IL-1β secretion and processing in response to DSS is mediated by the NLRP3 inflammasome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995461"], "description"=>"<div><p>As they undergo phagocytosis, most early apoptotic cells negatively regulate proinflammatory signaling and were suggested as a major mechanism in the resolution of inflammation. The dextran sulfate sodium model is generally viewed as an epithelial damage model suited to investigate innate immune responses. Macrophages primed with LPS and subsequently exposed to DSS secrete high levels of IL-1β in an NLRP3-, ASC-, and caspase-1-dependent manner. The aim of this research was to test the therapeutic effect of a single dose of apoptotic cells in a DSS-colitis model and to explore possible mechanisms. Primary peritoneal macrophages, the DSS mice model, and <i>Nlrp3</i>-deficient mice, were used to assess the effect apoptotic cells on colitis. Immunohistochemistry, flow-cytometer, and western blots helped to explore the effect and mechanisms. Using a variety of NLRP3 triggering mechanisms, we show that apoptotic cells negatively regulate NF-κB and NLRP3 activation in primary peritoneal macrophages, at pre- and post-transcription levels, via inhibition of reactive oxygen species, lysosomal stabilization, and blocking K+ efflux. This property of apoptotic cells is demonstrated in a dramatic clinical, histological, and immunological amelioration of DSS colitis in Balb/c and B6 mice following a single administration of apoptotic cells.</p></div>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361271, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Apoptotic_Cells_Induce_NF_954_B_and_Inflammasome_Negative_Signaling_/1361271", "title"=>"Apoptotic Cells Induce NF-κB and Inflammasome Negative Signaling", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995460"], "description"=>"<p><b>(A)</b> Flow-cytometer analysis of B6 pMΦ treated for 2h with apoptotic cells and/or 24h with DSS were stained with fluorochrome acridine orange (AO). Loss of fluorescence, which correlates with reduced numbers of lysosomes, was analyzed by flow-cytometer, excluding dead cells base on FSC/SSC parameters. Shown are means ± SEM of 4 independent experiments (*<i>p</i><0.05, **<i>p</i><0.03, one way ANOVA). <b>(B)</b> confocal microscopy of LPS primed pMΦ incubated (or not; left) for 2h with apoptotic cells (middle) or DAPI-stained apoptotic cells (right), stained with 1μg/mL acridine orange for 15 min and then incubated for 2.5 h with 3% DSS. Representative data from four experiments. <b>(C)</b> Apoptotic cell treatment inhibits nigericin-induced IL-1β secretion. B6 pMΦ cells were treated with nigericin at the indicated concentrations in the presence of LPS priming, with or without apoptotic cell treatment (*<i>p</i><0.01, unpaired t-test).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361270, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g007", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lysosomal_damage_and_K_efflux_in_pM_934_/1361270", "title"=>"Lysosomal damage and K+ efflux in pMΦ.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/1995456"], "description"=>"<p>(<b>A</b>) H&E appearance. (<b>A-I</b>) DSS uptake leads to severe epithelial damage (black arrowed) while (<b>A-II</b>) apoptotic cell treatment maintain integrity of treated mice (<b>A-III</b>) histological score of distal colon sections of DSS-treated Balb/c mice Results from 3 independent experiments (*<i>p</i><0.05, t-test). (<b>B</b>) Apoptotic cell treatment inhibits neutrophil accumulation in inflamed colon. Mouse colon tissue sections were stained by immunohistochemistry assay using a rabbit monoclonal antibody against mouse myeloperoxidase (MPO). After immunostaining, slides were counterstained by hematoxylin. Images show the MPO stain followed by HRP-anti rabbit secondary antibody. All images are x200. <b>(B-I)</b> Staining control. Untreated colon stained with HRP-anti rabbit secondary antibody only, without anti-MPO. <b>(B-II)</b> Normal colon control. MPO-stained neutrophils in untreated colon. <b>(B-III)</b> DSS treatment. MPO-stained neutrophils in 3% DSS treated colon (3% DSS+PBS). <b>(B-IV)</b> Apoptotic cell & DSS treatment. MPO-stained neutrophils in 3% DSS-treated colon with apoptotic cell infusion (3% DSS+ApoCell).</p>", "links"=>[], "tags"=>["mechanism", "lps", "apoptotic cells", "NLRP 3 activation", "Reactive oxygen species", "nf", "asc", "dextran sulfate sodium model", "B 6 mice", "il", "epithelial damage model", "effect apoptotic cells", "DSS mice model"], "article_id"=>1361266, "categories"=>["Biological Sciences"], "users"=>["Amir Grau", "Adi Tabib", "Inna Grau", "Inna Reiner", "Dror Mevorach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0122440.g004", "stats"=>{"downloads"=>9, "page_views"=>126, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histological_appearance_and_neutrophil_infiltration_of_distal_colon_sections_/1361266", "title"=>"Histological appearance and neutrophil infiltration of distal colon sections.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-30 03:58:55"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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