TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

• Published in: Cell death and differentiation 2011-08, Vol.18 (8), p.1316-1325
• Main Authors: Krysko, D V, Kaczmarek, A, Krysko, O, Heyndrickx, L, Woznicki, J, Bogaert, P, Cauwels, A, Takahashi, N, Magez, S, Bachert, C, Vandenabeele, P
• Format: Article
• Language: English
• Subjects: 631/250/256/2516; 631/250/262/2106/2108; 631/80/82/23; 631/92/436; Adenosine triphosphate; Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Apoptosis - immunology; Biochemistry; Biomedical and Life Sciences; Biomedical research; Caspase 1 - genetics; Caspase 1 - immunology; Cell Biology; Cell Cycle Analysis; Cell death; Cytokines; Doxorubicin - pharmacology; Female; Growth factors; Immune system; Inflammation - chemically induced; Inflammation - immunology; Life Sciences; Macrophages - cytology; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Monocytes - cytology; Monocytes - immunology; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Neutrophils; Original Paper; Physiology; Proteins; Sensors; Signal Transduction - immunology; Stem Cells; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.4

Anthracycline antibiotics are inducers of an immunogenic form of apoptosis that has immunostimulatory properties because of the release of damage-associated molecular patterns. To study the mechanisms used by the innate immune system to sense this immunogenic form of cell death, we established an in vivo model of cell death induced by intraperitoneal injection of doxorubicin, a prototype of anthracyclines. The acute sterile inflammation in this model is characterized by rapid influx of neutrophils and increased levels of IL-6 and monocyte chemotactic protein-1. We demonstrate that acute inflammation induced by doxorubicin is associated with apoptosis of monocytes/macrophages and that it is specific for doxorubicin, an immunogenic chemotherapeutic. Further, the inflammatory response is significantly reduced in mice deficient in myeloid differentiation primary response gene 88 (MyD88), TLR-2 or TLR-9. Importantly, a TLR-9 antagonist reduces the recruitment of neutrophils induced by doxorubicin. By contrast, the acute inflammatory response is not affected in TRIF Lps2 mutant mice and in TLR-3, TLR-4 and caspase-1 knockout mice, which shows that the inflammasome does not have a major role in doxorubicin-induced acute inflammation. Our findings provide important new insights into how the innate immune system senses immunogenic apoptotic cells and clearly demonstrate that the TLR-2/TLR-9-MyD88 signaling pathways have a central role in initiating the acute inflammatory response to this immunogenic form of apoptosis.