A blast without power – cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses

• Published in: Cell death and differentiation Vol. 23; no. 6; pp. 1016 - 1025
• Main Authors: Maueröder, C, Chaurio, R A, Dumych, T, Podolska, M, Lootsik, M D, Culemann, S, Friedrich, R P, Bilyy, R, Alexiou, C, Schett, G, Berens, C, Herrmann, M, Munoz, L E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2016; Nature Publishing Group
• Subjects: 13/31; 14/34; 14/63; 631/250/1933; 64/60; 82/80; 96/106; 96/21; Alarmins - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; BH3 Interacting Domain Death Agonist Protein - genetics; BH3 Interacting Domain Death Agonist Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caspase 3 - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Cytokines - analysis; Doxycycline - pharmacology; HMGB1 Protein - analysis; Interleukin-27 - analysis; Life Sciences; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Original Paper; Reactive Oxygen Species - metabolism; Spleen - cytology; Spleen - transplantation; Stem Cells; Toxins, Biological - genetics; Toxins, Biological - metabolism; Transplantation, Homologous; Ultraviolet Rays
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.4

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.