--- _id: '1142' abstract: - lang: eng text: Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders. acknowledgement: 'Y. Fukui (Medical Institute of Bioregulation, Kyushu University) and J. Stein (Theodor Kocher Institute, University of Bern) are acknowledged for providing the DOCK8 deficient bone marrow. and H. Häcker (St. Judes Children''s Research Hospital) for providing the ERHBD-HoxB8-encoding retroviral construct. pSpCas9(BB)-2a-Puro (PX459) was a gift from F. Zhang (Massachusetts Institute of Technology) (Addgene plasmid # 48139) and pGRG36 was a gift from N. Craig (Johns Hopkins University School of Medicine) (Addgene plasmid # 16666). LifeAct-GFP-encoding retrovirus was kindly provided by A. Leithner (Institute of Science and Technology Austria). pSIM8 and TKC E. coli were gifts from D.L. Court (Center for Cancer Research, National Cancer Institute). We acknowledge M. Gröger and S. Rauscher for excellent technical support (Core imaging facility, Medical University of Vienna). We thank D.P. Barlow and L.R. Cheever for critical reading of the manuscript. This work was supported by the Austrian Academy of Sciences, the Science Fund of the Austrian National Bank (14107) and the Austrian Science Fund FWF (I1620-B22) in the Infect-ERA framework (to S.Knapp).' author: - first_name: Rui full_name: Martins, Rui last_name: Martins - first_name: Julia full_name: Maier, Julia last_name: Maier - first_name: Anna full_name: Gorki, Anna last_name: Gorki - first_name: Kilian full_name: Huber, Kilian last_name: Huber - first_name: Omar full_name: Sharif, Omar last_name: Sharif - first_name: Philipp full_name: Starkl, Philipp last_name: Starkl - first_name: Simona full_name: Saluzzo, Simona last_name: Saluzzo - first_name: Federica full_name: Quattrone, Federica last_name: Quattrone - first_name: Riem full_name: Gawish, Riem last_name: Gawish - first_name: Karin full_name: Lakovits, Karin last_name: Lakovits - first_name: Michael full_name: Aichinger, Michael last_name: Aichinger - first_name: Branka full_name: Radic Sarikas, Branka last_name: Radic Sarikas - first_name: Charles full_name: Lardeau, Charles last_name: Lardeau - first_name: Anastasiya full_name: Hladik, Anastasiya last_name: Hladik - first_name: Ana full_name: Korosec, Ana last_name: Korosec - first_name: Markus full_name: Brown, Markus id: 3DAB9AFC-F248-11E8-B48F-1D18A9856A87 last_name: Brown - first_name: Kari full_name: Vaahtomeri, Kari id: 368EE576-F248-11E8-B48F-1D18A9856A87 last_name: Vaahtomeri orcid: 0000-0001-7829-3518 - first_name: Michelle full_name: Duggan, Michelle id: 2EDEA62C-F248-11E8-B48F-1D18A9856A87 last_name: Duggan - first_name: Dontscho full_name: Kerjaschki, Dontscho last_name: Kerjaschki - first_name: Harald full_name: Esterbauer, Harald last_name: Esterbauer - first_name: Jacques full_name: Colinge, Jacques last_name: Colinge - first_name: Stephanie full_name: Eisenbarth, Stephanie last_name: Eisenbarth - first_name: Thomas full_name: Decker, Thomas last_name: Decker - first_name: Keiryn full_name: Bennett, Keiryn last_name: Bennett - first_name: Stefan full_name: Kubicek, Stefan last_name: Kubicek - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 - first_name: Giulio full_name: Superti Furga, Giulio last_name: Superti Furga - first_name: Sylvia full_name: Knapp, Sylvia last_name: Knapp citation: ama: Martins R, Maier J, Gorki A, et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. 2016;17(12):1361-1372. doi:10.1038/ni.3590 apa: Martins, R., Maier, J., Gorki, A., Huber, K., Sharif, O., Starkl, P., … Knapp, S. (2016). Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. Nature Publishing Group. https://doi.org/10.1038/ni.3590 chicago: Martins, Rui, Julia Maier, Anna Gorki, Kilian Huber, Omar Sharif, Philipp Starkl, Simona Saluzzo, et al. “Heme Drives Hemolysis-Induced Susceptibility to Infection via Disruption of Phagocyte Functions.” Nature Immunology. Nature Publishing Group, 2016. https://doi.org/10.1038/ni.3590. ieee: R. Martins et al., “Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions,” Nature Immunology, vol. 17, no. 12. Nature Publishing Group, pp. 1361–1372, 2016. ista: Martins R, Maier J, Gorki A, Huber K, Sharif O, Starkl P, Saluzzo S, Quattrone F, Gawish R, Lakovits K, Aichinger M, Radic Sarikas B, Lardeau C, Hladik A, Korosec A, Brown M, Vaahtomeri K, Duggan M, Kerjaschki D, Esterbauer H, Colinge J, Eisenbarth S, Decker T, Bennett K, Kubicek S, Sixt MK, Superti Furga G, Knapp S. 2016. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. 17(12), 1361–1372. mla: Martins, Rui, et al. “Heme Drives Hemolysis-Induced Susceptibility to Infection via Disruption of Phagocyte Functions.” Nature Immunology, vol. 17, no. 12, Nature Publishing Group, 2016, pp. 1361–72, doi:10.1038/ni.3590. short: R. Martins, J. Maier, A. Gorki, K. Huber, O. Sharif, P. Starkl, S. Saluzzo, F. Quattrone, R. Gawish, K. Lakovits, M. Aichinger, B. Radic Sarikas, C. Lardeau, A. Hladik, A. Korosec, M. Brown, K. Vaahtomeri, M. Duggan, D. Kerjaschki, H. Esterbauer, J. Colinge, S. Eisenbarth, T. Decker, K. Bennett, S. Kubicek, M.K. Sixt, G. Superti Furga, S. Knapp, Nature Immunology 17 (2016) 1361–1372. date_created: 2018-12-11T11:50:22Z date_published: 2016-12-01T00:00:00Z date_updated: 2021-01-12T06:48:36Z day: '01' department: - _id: MiSi - _id: PeJo doi: 10.1038/ni.3590 intvolume: ' 17' issue: '12' language: - iso: eng main_file_link: - open_access: '1' url: https://ora.ox.ac.uk/objects/uuid:f53a464e-1e5b-4f08-a7d8-b6749b852b9d month: '12' oa: 1 oa_version: Submitted Version page: 1361 - 1372 publication: Nature Immunology publication_status: published publisher: Nature Publishing Group publist_id: '6216' quality_controlled: '1' scopus_import: 1 status: public title: Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 17 year: '2016' ... --- _id: '1150' abstract: - lang: eng text: When neutrophils infiltrate a site of inflammation, they have to stop at the right place to exert their effector function. In this issue of Developmental Cell, Wang et al. (2016) show that neutrophils sense reactive oxygen species via the TRPM2 channel to arrest migration at their target site. © 2016 Elsevier Inc. author: - first_name: Jörg full_name: Renkawitz, Jörg id: 3F0587C8-F248-11E8-B48F-1D18A9856A87 last_name: Renkawitz orcid: 0000-0003-2856-3369 - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 citation: ama: Renkawitz J, Sixt MK. A Radical Break Restraining Neutrophil Migration. Developmental Cell. 2016;38(5):448-450. doi:10.1016/j.devcel.2016.08.017 apa: Renkawitz, J., & Sixt, M. K. (2016). A Radical Break Restraining Neutrophil Migration. Developmental Cell. Cell Press. https://doi.org/10.1016/j.devcel.2016.08.017 chicago: Renkawitz, Jörg, and Michael K Sixt. “A Radical Break Restraining Neutrophil Migration.” Developmental Cell. Cell Press, 2016. https://doi.org/10.1016/j.devcel.2016.08.017. ieee: J. Renkawitz and M. K. Sixt, “A Radical Break Restraining Neutrophil Migration,” Developmental Cell, vol. 38, no. 5. Cell Press, pp. 448–450, 2016. ista: Renkawitz J, Sixt MK. 2016. A Radical Break Restraining Neutrophil Migration. Developmental Cell. 38(5), 448–450. mla: Renkawitz, Jörg, and Michael K. Sixt. “A Radical Break Restraining Neutrophil Migration.” Developmental Cell, vol. 38, no. 5, Cell Press, 2016, pp. 448–50, doi:10.1016/j.devcel.2016.08.017. short: J. Renkawitz, M.K. Sixt, Developmental Cell 38 (2016) 448–450. date_created: 2018-12-11T11:50:25Z date_published: 2016-09-12T00:00:00Z date_updated: 2021-01-12T06:48:39Z day: '12' department: - _id: MiSi doi: 10.1016/j.devcel.2016.08.017 intvolume: ' 38' issue: '5' language: - iso: eng month: '09' oa_version: None page: 448 - 450 publication: Developmental Cell publication_status: published publisher: Cell Press publist_id: '6208' quality_controlled: '1' scopus_import: 1 status: public title: A Radical Break Restraining Neutrophil Migration type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 38 year: '2016' ... --- _id: '1154' abstract: - lang: eng text: "Cellular locomotion is a central hallmark of eukaryotic life. It is governed by cell-extrinsic molecular factors, which can either emerge in the soluble phase or as immobilized, often adhesive ligands. To encode for direction, every cue must be present as a spatial or temporal gradient. Here, we developed a microfluidic chamber that allows measurement of cell migration in combined response to surface immobilized and soluble molecular gradients. As a proof of principle we study the response of dendritic cells to their major guidance cues, chemokines. The majority of data on chemokine gradient sensing is based on in vitro studies employing soluble gradients. Despite evidence suggesting that in vivo chemokines are often immobilized to sugar residues, limited information is available how cells respond to immobilized chemokines. We tracked migration of dendritic cells towards immobilized gradients of the chemokine CCL21 and varying superimposed soluble gradients of CCL19. Differential migratory patterns illustrate the potential of our setup to quantitatively study the competitive response to both types of gradients. Beyond chemokines our approach is broadly applicable to alternative systems of chemo- and haptotaxis such as cells migrating along gradients of adhesion receptor ligands vs. any soluble cue. \r\n" acknowledgement: 'This work was supported by the Swiss National Science Foundation (Ambizione fellowship; PZ00P3-154733 to M.M.), the Swiss Multiple Sclerosis Society (research support to M.M.), a fellowship from the Boehringer Ingelheim Fonds (BIF) to J.S., the European Research Council (grant ERC GA 281556) and a START award from the Austrian Science Foundation (FWF) to M.S. #BioimagingFacility' article_number: '36440' author: - first_name: Jan full_name: Schwarz, Jan id: 346C1EC6-F248-11E8-B48F-1D18A9856A87 last_name: Schwarz - first_name: Veronika full_name: Bierbaum, Veronika id: 3FD04378-F248-11E8-B48F-1D18A9856A87 last_name: Bierbaum - first_name: Jack full_name: Merrin, Jack id: 4515C308-F248-11E8-B48F-1D18A9856A87 last_name: Merrin orcid: 0000-0001-5145-4609 - first_name: Tino full_name: Frank, Tino last_name: Frank - first_name: Robert full_name: Hauschild, Robert id: 4E01D6B4-F248-11E8-B48F-1D18A9856A87 last_name: Hauschild orcid: 0000-0001-9843-3522 - first_name: Mark Tobias full_name: Bollenbach, Mark Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X - first_name: Savaş full_name: Tay, Savaş last_name: Tay - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 - first_name: Matthias full_name: Mehling, Matthias id: 3C23B994-F248-11E8-B48F-1D18A9856A87 last_name: Mehling orcid: 0000-0001-8599-1226 citation: ama: Schwarz J, Bierbaum V, Merrin J, et al. A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. 2016;6. doi:10.1038/srep36440 apa: Schwarz, J., Bierbaum, V., Merrin, J., Frank, T., Hauschild, R., Bollenbach, M. T., … Mehling, M. (2016). A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. Nature Publishing Group. https://doi.org/10.1038/srep36440 chicago: Schwarz, Jan, Veronika Bierbaum, Jack Merrin, Tino Frank, Robert Hauschild, Mark Tobias Bollenbach, Savaş Tay, Michael K Sixt, and Matthias Mehling. “A Microfluidic Device for Measuring Cell Migration towards Substrate Bound and Soluble Chemokine Gradients.” Scientific Reports. Nature Publishing Group, 2016. https://doi.org/10.1038/srep36440. ieee: J. Schwarz et al., “A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients,” Scientific Reports, vol. 6. Nature Publishing Group, 2016. ista: Schwarz J, Bierbaum V, Merrin J, Frank T, Hauschild R, Bollenbach MT, Tay S, Sixt MK, Mehling M. 2016. A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. 6, 36440. mla: Schwarz, Jan, et al. “A Microfluidic Device for Measuring Cell Migration towards Substrate Bound and Soluble Chemokine Gradients.” Scientific Reports, vol. 6, 36440, Nature Publishing Group, 2016, doi:10.1038/srep36440. short: J. Schwarz, V. Bierbaum, J. Merrin, T. Frank, R. Hauschild, M.T. Bollenbach, S. Tay, M.K. Sixt, M. Mehling, Scientific Reports 6 (2016). date_created: 2018-12-11T11:50:27Z date_published: 2016-11-07T00:00:00Z date_updated: 2021-01-12T06:48:41Z day: '07' ddc: - '579' department: - _id: MiSi - _id: NanoFab - _id: Bio - _id: ToBo doi: 10.1038/srep36440 ec_funded: 1 file: - access_level: open_access content_type: application/pdf creator: system date_created: 2018-12-12T10:09:32Z date_updated: 2018-12-12T10:09:32Z file_id: '4756' file_name: IST-2017-744-v1+1_srep36440.pdf file_size: 2353456 relation: main_file file_date_updated: 2018-12-12T10:09:32Z has_accepted_license: '1' intvolume: ' 6' language: - iso: eng month: '11' oa: 1 oa_version: Published Version project: - _id: 25A603A2-B435-11E9-9278-68D0E5697425 call_identifier: FP7 grant_number: '281556' name: Cytoskeletal force generation and force transduction of migrating leukocytes (EU) - _id: 25A8E5EA-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: Y 564-B12 name: Cytoskeletal force generation and transduction of leukocytes (FWF) publication: Scientific Reports publication_status: published publisher: Nature Publishing Group publist_id: '6204' pubrep_id: '744' quality_controlled: '1' scopus_import: 1 status: public title: A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 6 year: '2016' ... --- _id: '1201' abstract: - lang: eng text: In this issue of Cell, Skau et al. show that the formin FMN2 organizes a perinuclear actin cytoskeleton that protects the nucleus and its genomic content of migrating cells squeezing through small spaces. author: - first_name: Jörg full_name: Renkawitz, Jörg id: 3F0587C8-F248-11E8-B48F-1D18A9856A87 last_name: Renkawitz orcid: 0000-0003-2856-3369 - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 citation: ama: Renkawitz J, Sixt MK. Formin’ a nuclear protection. Cell. 2016;167(6):1448-1449. doi:10.1016/j.cell.2016.11.024 apa: Renkawitz, J., & Sixt, M. K. (2016). Formin’ a nuclear protection. Cell. Cell Press. https://doi.org/10.1016/j.cell.2016.11.024 chicago: Renkawitz, Jörg, and Michael K Sixt. “Formin’ a Nuclear Protection.” Cell. Cell Press, 2016. https://doi.org/10.1016/j.cell.2016.11.024. ieee: J. Renkawitz and M. K. Sixt, “Formin’ a nuclear protection,” Cell, vol. 167, no. 6. Cell Press, pp. 1448–1449, 2016. ista: Renkawitz J, Sixt MK. 2016. Formin’ a nuclear protection. Cell. 167(6), 1448–1449. mla: Renkawitz, Jörg, and Michael K. Sixt. “Formin’ a Nuclear Protection.” Cell, vol. 167, no. 6, Cell Press, 2016, pp. 1448–49, doi:10.1016/j.cell.2016.11.024. short: J. Renkawitz, M.K. Sixt, Cell 167 (2016) 1448–1449. date_created: 2018-12-11T11:50:41Z date_published: 2016-12-01T00:00:00Z date_updated: 2021-01-12T06:49:03Z day: '01' department: - _id: MiSi doi: 10.1016/j.cell.2016.11.024 intvolume: ' 167' issue: '6' language: - iso: eng month: '12' oa_version: None page: 1448 - 1449 publication: Cell publication_status: published publisher: Cell Press publist_id: '6149' quality_controlled: '1' scopus_import: 1 status: public title: Formin’ a nuclear protection type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 167 year: '2016' ... --- _id: '1217' abstract: - lang: eng text: Understanding the regulation of T-cell responses during inflammation and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E 2 (PGE 2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE 2 during T-cell receptor stimulation. In addition, we show that autocrine PGE 2 signaling through EP receptors is essential for optimal CD4 + T-cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE 2 was found to provide additive co-stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell-dendritic cell (DC) interactions and Th-cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen-induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T-cell activation, accompanied by a decline in activated and interferon-γ-producing CD4 + Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE 2, which in turn provide additive co-stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE 2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T-cell activation and development of T cell-mediated inflammatory responses. This may have implications in various pathophysiological settings. acknowledgement: This manuscript has been supported by grants SAF2007-61716 and S-SAL-0159/2006 awarded by the Spanish Ministry of Science and Education and the Community of Madrid to Dr M Fresno. author: - first_name: Vinatha full_name: Sreeramkumar, Vinatha last_name: Sreeramkumar - first_name: Miroslav full_name: Hons, Miroslav id: 4167FE56-F248-11E8-B48F-1D18A9856A87 last_name: Hons orcid: 0000-0002-6625-3348 - first_name: Carmen full_name: Punzón, Carmen last_name: Punzón - first_name: Jens full_name: Stein, Jens last_name: Stein - first_name: David full_name: Sancho, David last_name: Sancho - first_name: Manuel full_name: Fresno Forcelledo, Manuel last_name: Fresno Forcelledo - first_name: Natalia full_name: Cuesta, Natalia last_name: Cuesta citation: ama: Sreeramkumar V, Hons M, Punzón C, et al. Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors. Immunology and Cell Biology. 2016;94(1):39-51. doi:10.1038/icb.2015.62 apa: Sreeramkumar, V., Hons, M., Punzón, C., Stein, J., Sancho, D., Fresno Forcelledo, M., & Cuesta, N. (2016). Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors. Immunology and Cell Biology. Nature Publishing Group. https://doi.org/10.1038/icb.2015.62 chicago: Sreeramkumar, Vinatha, Miroslav Hons, Carmen Punzón, Jens Stein, David Sancho, Manuel Fresno Forcelledo, and Natalia Cuesta. “Efficient T-Cell Priming and Activation Requires Signaling through Prostaglandin E2 (EP) Receptors.” Immunology and Cell Biology. Nature Publishing Group, 2016. https://doi.org/10.1038/icb.2015.62. ieee: V. Sreeramkumar et al., “Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors,” Immunology and Cell Biology, vol. 94, no. 1. Nature Publishing Group, pp. 39–51, 2016. ista: Sreeramkumar V, Hons M, Punzón C, Stein J, Sancho D, Fresno Forcelledo M, Cuesta N. 2016. Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors. Immunology and Cell Biology. 94(1), 39–51. mla: Sreeramkumar, Vinatha, et al. “Efficient T-Cell Priming and Activation Requires Signaling through Prostaglandin E2 (EP) Receptors.” Immunology and Cell Biology, vol. 94, no. 1, Nature Publishing Group, 2016, pp. 39–51, doi:10.1038/icb.2015.62. short: V. Sreeramkumar, M. Hons, C. Punzón, J. Stein, D. Sancho, M. Fresno Forcelledo, N. Cuesta, Immunology and Cell Biology 94 (2016) 39–51. date_created: 2018-12-11T11:50:46Z date_published: 2016-01-01T00:00:00Z date_updated: 2021-01-12T06:49:09Z day: '01' department: - _id: MiSi doi: 10.1038/icb.2015.62 intvolume: ' 94' issue: '1' language: - iso: eng month: '01' oa_version: None page: 39 - 51 publication: Immunology and Cell Biology publication_status: published publisher: Nature Publishing Group publist_id: '6116' quality_controlled: '1' scopus_import: 1 status: public title: Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 94 year: '2016' ...