Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada.
Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6G 2V4, Canada
J Immunol. 2014 Aug 1;193(3):1333-43. doi: 10.4049/jimmunol.1400420. Epub 2014 Jun 27.
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.
预先暴露于炭疽致死毒素（LeTx）亚致死剂量的巨噬细胞对随后的高细胞毒性 LeTx 剂量无反应，称为毒素诱导的抗性（TIR）。一小部分 TIR 细胞（2-4%）保留 TIR 特征长达 5-6 周。通过研究这些长期 TIR 细胞，我们发现高水平的组蛋白去乙酰化酶（HDAC）8 的表达对于 TIR 至关重要。通过小干扰 RNA 或 HDAC8 特异性抑制剂 PCI-34051 敲低或抑制 HDAC8，分别诱导线粒体死亡基因 Bcl2 腺病毒 E1B 19 kDa 相互作用蛋白 3（BNIP3）、BNIP3 样和转移性淋巴结 64 的表达，并使 TIR 细胞对 LeTx 重新敏感。在多种组蛋白乙酰化中，组蛋白 H3 赖氨酸 27（H3K27）乙酰化在 TIR 细胞中以依赖于 HDAC8 的方式显著降低，并且 H3K27 乙酰化与 BNIP3 和转移性淋巴结 64 的基因组区域的关联在 TIR 细胞中减弱，HDAC8 被募集到这些区域。此外，HDAC8 的过表达或敲低组蛋白乙酰转移酶 CREB 结合蛋白/ p300（已知靶向 H3K27），使野生型细胞对 LeTx 产生抗性。与 RAW264.7 细胞一样，暴露于 LeTx 亚致死剂量的原代骨髓来源巨噬细胞以依赖于 HDAC8 的方式对 LeTx 产生抗性。总之，这项研究表明，HDAC8 介导的表观遗传重编程在决定巨噬细胞中 LeTx 诱导的细胞焦亡的易感性方面起着关键作用。
