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  • The American Association of Immunologists  (16)
  • 1
    Online Resource
    Online Resource
    IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 203, No. 6 ( 2019-09-15), p. 1457-1467
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 203, No. 6 ( 2019-09-15), p. 1457-1467
    Abstract: IL-33 is an IL-1 family member protein that is a potent driver of inflammatory responses in both allergic and nonallergic disease. This proinflammatory effect is mediated primarily by extracellular release of IL-33 from stromal cells and binding of the C-terminal domain of IL-33 to its receptor ST2 on targets such as CD4+ Th2 cells, ILC2, and mast cells. Notably, IL-33 has a distinct N-terminal domain that mediates nuclear localization and chromatin binding. However, a defined in vivo cell-intrinsic role for IL-33 has not been established. We identified IL-33 expression in the nucleus of progenitor B (pro-B) and large precursor B cells in the bone marrow, an expression pattern unique to B cells among developing lymphocytes. The IL-33 receptor ST2 was not expressed within the developing B cell lineage at either the transcript or protein level. RNA sequencing analysis of wild-type and IL-33–deficient pro-B and large precursor B cells revealed a unique, IL-33–dependent transcriptional profile wherein IL-33 deficiency led to an increase in E2F targets, cell cycle genes, and DNA replication and a decrease in the p53 pathway. Using mixed bone marrow chimeric mice, we demonstrated that IL-33 deficiency resulted in an increased frequency of developing B cells via a cell-intrinsic mechanism starting at the pro-B cell stage paralleling IL-33 expression. Finally, IL-33 was detectable during early B cell development in humans and IL33 mRNA expression was decreased in B cell chronic lymphocytic leukemia samples compared with healthy controls. Collectively, these data establish a cell-intrinsic, ST2-independent role for IL-33 in early B cell development.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900408
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 206, No. 6 ( 2021-03-15), p. 1127-1139
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 6 ( 2021-03-15), p. 1127-1139
    Abstract: T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17–producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4– and IL-17–producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2001029
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Metabolic characteristics of Th2 and Th17 cells drive airway inflammation
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 73.3-73.3
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 73.3-73.3
    Abstract: Asthma is an airway inflammatory disease that is mediated by T effector (Teff) cells, specifically Th2 and Th17 cells. Increases in disease severity leading to neutrophilic asthma is characterized by a shift towards a higher Th17 response. Typical treatment of asthmatic patients include the use of glucocoriticoid (GC) steroids. These drugs are effective at controlling inflammation in mild cases but as disease severity increases towards neutrophilic disease there is resistance by Th17 cells to the effects of these drugs. A key therapeutic objective is to identify either alternative treatments for asthma or targets that make Th17 cells more susceptible to GCs. Studies have shown that cells that have increased glycolysis and oxidative phosphorylation are more resistant to the effects of GCs. We hypothesized that the intrinsic metabolic phenotype of Th17 cells allow them to be more resistant to GCs. In this study we show, that in the murine model of airway inflammation there are differences in the expression of metabolic proteins between Th2 and Th17 cells that are present in the lung. Additionally, we show that metabolic inhibitors alter the functionality of the Teff cells and can be a target to restore sensitivity to GCs. We have also performed CyTOF analysis of asthmatic patients’ PBMCs, these data demonstrate a much higher metabolic phenotype of asthmatic patients when compared to healthy controls. Overall our studies suggest that metabolic inhibition may be a viable therapeautic in conjuction with GCs in order to dampen the function of Teffs in the airway.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.73.3
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Androgen receptor signaling decreases glutaminolysis in Th17 cells to reduce airway inflammation in asthma
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 109.11-109.11
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 109.11-109.11
    Abstract: Women have higher rates of severe asthma compared to men. Severe asthma has increased Th2-mediated eosinophilic and/or Th17-mediated neutrophilic airway inflammation. We showed androgens, signaling through the androgen receptor (AR), decreased Th2- and Th17-mediated airway inflammation, and that Th17 and Th2 rely on glutaminolysis during allergic airway inflammation. Therefore, we hypothesized that AR signaling decreases glutaminolysis in Th2 and Th17 cells, resulting in decreased airway inflammation. Th2 and Th17 were differentiated in vitro from wild-type male and ArTfm male mice, with a nonfunctional AR. Mitochondrial metabolism and glycolysis were determined by measuring oxygen consumption rate (OCR), reactive oxygen species (ROS), and the extracellular acidification rate (ECAR). In Th17 cells, AR signaling decreased OCR, while increasing mitochondrial ROS, suggesting decreased glutaminolysis. Further, both 5α-DHT (0.1nM) and CB839 (a glutaminase inhibitor, 0.5μM) reduced OCR in Th17 cells from male mice. AR signaling had no effect on ECAR in Th17 cells or OCR and ECAR in Th2 cells. To induce eosinophilic and neutrophilic airway inflammation, house dust mite (HDM) was intranasally administered to ArfloxedCD4-Cre and Arfloxed male mice and markers of glycolysis and glutaminolysis were determined by flow cytometry. AR signaling decreased airway neutrophils, the number of Th17 lung cells, and GLUD1, a glutaminolysis marker, expression in T cells, but had no effect on eosinophils or Th2 cells. Combined, these data showed that AR signaling decreased glutaminolysis in Th17, but not Th2, cells. Understanding these pathways may provide new potential therapeutic targets in women with difficult-to-treat asthma. Supported by grants from NIH (R01 HL12254, R01 HL136664, T32 GM007347)  
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.109.11
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    The PGI2 Analog Cicaprost Inhibits IL-33–Induced Th2 Responses, IL-2 Production, and CD25 Expression in Mouse CD4+ T Cells
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 201, No. 7 ( 2018-10-01), p. 1936-1945
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 201, No. 7 ( 2018-10-01), p. 1936-1945
    Abstract: IL-33 has pleiotropic functions in immune responses and promotes the development of allergic diseases and asthma. IL-33 induces Th2 differentiation and enhances type 2 cytokine production by CD4+ T cells. However, the regulation of IL-33–driven type 2 cytokine responses is not fully defined. In this study, we investigated the effect of PGI2, a lipid mediator formed in the cyclooxygenase pathway of arachidonic acid metabolism, on naive CD4+ T cell activation, proliferation, and differentiation by IL-33. Using wild-type and PGI2 receptor (IP) knockout mice, we found that the PGI2 analog cicaprost dose-dependently inhibited IL-33–driven IL-4, IL-5, and IL-13 production by CD4+ T cells in an IP-specific manner. In addition, cicaprost inhibited IL-33–driven IL-2 production and CD25 expression by CD4+ T cells. Furthermore, IP knockout mice had increased IL-5 and IL-13 responses of CD4+ T cells to Alternaria sensitization and challenge in mouse lungs. Because IL-33 is critical for Alternaria-induced type 2 responses, these data suggest that PGI2 not only inhibits IL-33–stimulated CD4+ Th2 cell responses in vitro but also suppresses IL-33–induced Th2 responses caused by protease-containing allergens in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700605
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    COX inhibition enhances allergen-induced IL-33 release and ILC2 responses in mouse lungs
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 148.11-148.11
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 148.11-148.11
    Abstract: The cyclooxygenase (COX) metabolic pathway has regulatory functions in immune responses and inflammation. However, the effect of the COX pathway on innate airway inflammation induced by protease-containing allergens such as Alternaria alternata is not fully defined. Here we show that COX inhibition augmented innate lung type 2 responses after repeated airway exposures to Alternaria extract in mice. We treated wild type BALB/c and IL-33 KO mice with either the COX inhibitor indomethacin or vehicle in drinking water and challenged mice intranasally with Alternaria extract for 4 consecutive days to induce innate lung inflammation. We found that indomethacin significantly increased the numbers of group 2 innate lymphoid cells (ILC2) and IL-5+IL-13+ ILC2 in the lung. Indomethacin also increased type 2 cytokine (IL-5 and IL-13) responses, the percentages of eosinophils, and mucus production in the lung. IL-33 is required for Alt-induced lung ILC2 responses, and indomethacin did not change IL-5 and IL-13 expression in IL-33 KO mice. Consistently, indomethacin increased the release of IL-33 in bronchoalveolar lavage fluid after Alternaria challenge, suggesting that more IL-33 was available for ILC2 activation. Indomethacin also increased reactive oxygen species (ROS) production in the lung, providing a possible mechanism for the increased IL-33 release. Although contrasting effects of PGD2 and PGE2/PGI2 on ILC2 responses have been previously reported, the overall effect of COX pathway on ILC2 function is inhibitory in Alternaria extract-induced airway innate type 2 responses.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.148.11
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 199, No. 2 ( 2017-07-15), p. 510-519
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 199, No. 2 ( 2017-07-15), p. 510-519
    Abstract: The appropriate orchestration of different arms of the immune response is critical during viral infection to promote efficient viral clearance while limiting immunopathology. However, the signals and mechanisms that guide this coordination are not fully understood. IFNs are produced at high levels during viral infection and have convergent signaling through STAT1. We hypothesized that STAT1 signaling during viral infection regulates the balance of innate lymphoid cells (ILC), a diverse class of lymphocytes that are poised to respond to environmental insults including viral infections with the potential for both antiviral or immunopathologic functions. During infection with respiratory syncytial virus (RSV), STAT1-deficient mice had reduced numbers of antiviral IFN-γ+ ILC1 and increased numbers of immunopathologic IL-5+ and IL-13+ ILC2 and IL-17A+ ILC3 compared with RSV-infected wild-type mice. Using bone marrow chimeric mice, we found that both ILC-intrinsic and ILC-extrinsic factors were responsible for this ILC dysregulation during viral infection in STAT1-deficient mice. Regarding ILC-extrinsic mechanisms, we found that STAT1-deficient mice had significantly increased expression of IL-33 and IL-23, cytokines that promote ILC2 and ILC3, respectively, compared with wild-type mice during RSV infection. Moreover, disruption of IL-33 or IL-23 signaling attenuated cytokine-producing ILC2 and ILC3 responses in STAT1-deficient mice during RSV infection. Collectively, these data demonstrate that STAT1 is a key orchestrator of cytokine-producing ILC responses during viral infection via ILC-extrinsic regulation of IL-33 and IL-23.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1601984
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
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  • 8
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    Online Resource
    STAT1 Negatively Regulates Lung Basophil IL-4 Expression Induced by Respiratory Syncytial Virus Infection
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 183, No. 3 ( 2009-08-01), p. 2016-2026
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 183, No. 3 ( 2009-08-01), p. 2016-2026
    Abstract: IL-4 contributes to immunopathology induced in mice by primary respiratory syncytial virus (RSV) infection. However, the cellular source of IL-4 in RSV infection is unknown. We identified CD3−CD49b+ cells as the predominant source of IL-4 in the lungs of RSV-infected BALB/c mice. We ruled out T cells, NK cells, NKT cells, mast cells, and eosinophils as IL-4 expressors in RSV infection by flow cytometry. Using IL4 GFP reporter mice (4get) mice, we identified the IL-4-expressing cells in RSV infection as basophils (CD3−CD49b+FcεRI+c-kit−). Because STAT1−/− mice have an enhanced Th2-type response to RSV infection, we also sought to determine the cellular source and role of IL-4 in RSV-infected STAT1−/− mice. RSV infection resulted in significantly more IL-4-expressing CD3−CD49b+ cells in the lungs of STAT1−/− mice than in BALB/c mice. CD49b+IL-4+ cells sorted from the lungs of RSV-infected STAT1−/− mice and stained with Wright-Giemsa had basophil characteristics. As in wild-type BALB/c mice, IL-4 contributed to lung histopathology in RSV-infected STAT1−/− mice. Depletion of basophils in RSV-infected STAT1−/− mice reduced lung IL-4 expression. Thus, we show for the first time that a respiratory virus (RSV) induced basophil accumulation in vivo. Basophils were the primary source of IL-4 in the lung in RSV infection, and STAT1 was a negative regulator of virus-induced basophil IL-4 expression.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0803167
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
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  • 9
    Online Resource
    Online Resource
    IL-13 Regulates Th17 Secretion of IL-17A in an IL-10–Dependent Manner
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 188, No. 3 ( 2012-02-01), p. 1027-1035
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 188, No. 3 ( 2012-02-01), p. 1027-1035
    Abstract: IL-13 is a central mediator of airway hyperresponsiveness and mucus expression, both hallmarks of asthma. IL-13 is found in the sputum of patients with asthma; therefore, IL-13 is an attractive drug target for treating asthma. We have shown previously that IL-13 inhibits Th17 cell production of IL-17A and IL-21 in vitro. Th17 cells are associated with autoimmune diseases, host immune responses, and severe asthma. In this study, we extend our in vitro findings and determine that IL-13 increases IL-10 production from Th17-polarized cells and that IL-13–induced IL-10 production negatively regulates the secretion of IL-17A and IL-21. To determine if IL-13 negatively regulates lung IL-17A expression via an IL-10–dependent mechanism in vivo, we used a model of respiratory syncytial virus (RSV) strain A2 infection in STAT1 knockout (KO) mice that increases lung IL-17A and IL-13 expression, cytokines not produced during RSV infection in wild-type mice. To test the hypothesis that IL-13 negatively regulates lung IL-17A expression, we created STAT1/IL-13 double KO (DKO) mice. We found that RSV-infected STAT1/IL-13 DKO mice had significantly greater lung IL-17A expression compared with that of STAT1 KO mice and that increased IL-17A expression was abrogated by anti-IL-10 Ab treatment. RSV-infected STAT1/IL-13 DKO mice also had increased neutrophil infiltration compared with that of RSV-infected STAT1 KO mice. Neutralizing IL-10 increased the infiltration of inflammatory cells into the lungs of STAT1 KO mice but not STAT1/IL-13 DKO mice. These findings are vital to understanding the potential side effects of therapeutics targeting IL-13. Inhibiting IL-13 may decrease IL-10 production and increase IL-17A production, thus potentiating IL-17A–associated diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1102216
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 10
    Online Resource
    Online Resource
    The PGI2 signaling pathway decreases glycolysis and mitochondria respiration in mouse Th2 cells
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 169.05-169.05
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 169.05-169.05
    Abstract: Prostaglandin I2 (PGI2) is a lipid molecule produced in the cyclooxygenase (COX) metabolic pathway and regulates T cell function and inflammation. We have previously shown that PGI2 inhibited type 2 cytokine production by Th2 cells in vitro and in vivo. To further investigate the mechanism of the inhibitory effect of PGI2 on Th2 differentiation, we determined the effect of the PGI2 analog cicaprost on T cell metabolism under Th2 conditions. Mouse naïve CD4 T cells from the spleen were activated with antibodies against CD3 and CD28 under Th2 polarization conditions and treated with cicaprost or vehicle for 4 days. Seahorse assays measured cellular glycolysis and mitochondria respiration. We found that cicaprost significantly decreased basal and maximum glycolysis in Th2 cells. Furthermore, when we performed Seahorse assays on the cells rested for 2 days after the initial 4 day T cell activation, we discovered that cicaprost not only suppressed basal glycolysis and glycolytic reserve but also dose-dependently inhibited basal and maximum mitochondria respiration. These results suggest that the PGI2 signaling pathway inhibits Th2 cell metabolism, providing a possible mechanism for PGI2-mediated inhibition of Th2 differentiation and Th2 cell-dependent immune disorders. The Department of Veterans Affairs BX004299 (RSP), NIH AI095227 (RSP), NIH AI111820 (RSP), NIH AI145265 (RSP), NIH AI124456 (RSP), NIH AI145397 (RSP).
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.169.05
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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