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HDAC8-mediated epigenetic reprogramming plays a key role in resistance to anthrax lethal toxin-induced pyroptosis in macrophages (Accepted in Journal of Immunology)

Macrophages pre-exposed to a sub-lethal dose of anthrax lethal toxin (LeTx) are refractory to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). We found that a high level of histone deacetylase (HDAC)8 expression is crucial for TIR, through suppressing the expression of the mitochondrial death genes Bcl2 Adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like (BNIP3L) and Metastatic Lymph Node (MLN)64, and re-sensitized TIR cells to LeTx. HDAC8 targets and deacetylates histone H3 lysine 27 acetylation (H3K27Ac), which results in closed chromatin comformation in the genomic regions of BNIP3 and MLN64. As in RAW264.7 cells, primary bone marrow-derived macrophages exposed to a sub-lethal dose of LeTx are resistance to LeTx in an HDAC8-dependent manner. Collectively, our study demonstrates that epigenetic reprogramming mediated by HDAC8 plays a key role in determining the susceptibility of LeTx-induced pyroptosis in macrophages.

    

G-CSF preferentially supports the generation of gut-homing Gr-1high macrophages in M-CSF-treated bone marrow cells

The granulocyte colony-stimulating factor (G-CSF) is best known for its activity in the generation and activation of neutrophils. However, our understanding on the role of G-CSF in macrophage development is limited. We found that G-CSF promotes the generation of Gr-1high/F4/80+ macrophage-like cells in macrophage colony-stimulating factor (M-CSF)-treated bone marrow cells (M-BMCs), likely through suppressing cell death and enhancing generation of Gr-1high/F4/80+ macrophage-like cells. These Gr-1high macrophage-like cells produced Ħ°M2-likeĦħ cells with a dominant gut-homing phenotype. These results suggest a novel function of G-CSF in the generation of gut-homing M2-like macrophages.