title: HDAC8-mediated epigenetic reprogramming plays a key role in resistance to anthrax lethal toxin-induced pyroptosis in macrophages.
abstract: Macrophages pre-exposed to a sublethal dose of anthrax lethal toxin (LeTx) are refractory to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). A small population of TIR cells (2-4%) retains TIR characteristics for up to 5-6 wk. Through studying these long-term TIR cells, we found that a high level of histone deacetylase (HDAC)8 expression was crucial for TIR. Knocking down or inhibition of HDAC8 by small interfering RNAs or the HDAC8-specific inhibitor PCI-34051, respectively, induced expression of the mitochondrial death genes Bcl2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like and metastatic lymph node 64, and resensitized TIR cells to LeTx. Among multiple histone acetylations, histone H3 lysine 27 (H3K27) acetylation was most significantly decreased in TIR cells in an HDAC8-dependent manner, and the association of H3K27 acetylation with the genomic regions of BNIP3 and metastatic lymph node 64, where HDAC8 was recruited to, was diminished in TIR cells. Furthermore, overexpression of HDAC8 or knocking down the histone acetyltransferase CREB-binding protein/p300, known to target H3K27, rendered wild-type cells resistant to LeTx. As in RAW264.7 cells, primary bone marrow-derived macrophages exposed to a sublethal dose of LeTx were resistant to LeTx in an HDAC8-dependent manner. Collectively, this study demonstrates that epigenetic reprogramming mediated by HDAC8 plays a key role in determining the susceptibility of LeTx-induced pyroptosis in macrophages.
authors: Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors: Soon-Duck
authors: SD
authors: Ha
authors: Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors: Chae Young
authors: CY
authors: Han
authors: Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors: Chantelle
authors: C
authors: Reid
authors: Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada sung.kim@schulich.uwo.ca.
authors: Sung Ouk
authors: SO
authors: Kim
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001427:Bacterial Toxins / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D057890:Epigenomics / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000077767:Panobinostat; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D012097:Repressor Proteins; C030325:anthrax toxin; D000077767:Panobinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases