title: A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses.
abstract: In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response.
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Maueröder
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: R A
authors.initials: RA
authors.lastname: Chaurio
authors.affiliation: Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.|Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine.
authors.forename: T
authors.initials: T
authors.lastname: Dumych
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Podolska
authors.affiliation: Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.|Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine.
authors.forename: M D
authors.initials: MD
authors.lastname: Lootsik
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Culemann
authors.affiliation: ENT Clinic, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Erlangen, Germany.
authors.forename: R P
authors.initials: RP
authors.lastname: Friedrich
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.|Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
authors.forename: R
authors.identifier: 0000-0002-2344-1349
authors.initials: R
authors.lastname: Bilyy
authors.affiliation: ENT Clinic, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Alexiou
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schett
authors.affiliation: Institute of Molecular Pathogenesis, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Berens
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: L E
authors.initials: LE
authors.lastname: Munoz
mesh_terms: D000067531:Alarmins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis; D004318:Doxycycline / Q000494:pharmacology; D024243:HMGB1 Protein / Q000032:analysis; D064094:Interleukin-27 / Q000032:analysis; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D014118:Toxins, Biological / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D014466:Ultraviolet Rays
chemical_list: D000067531:Alarmins; D051023:BH3 Interacting Domain Death Agonist Protein; D016207:Cytokines; D024243:HMGB1 Protein; D064094:Interleukin-27; D017382:Reactive Oxygen Species; D014118:Toxins, Biological; D053148:Caspase 3; D004318:Doxycycline