Histone Deacetylase 6 at Crossroads of Invection and Innate Immunity

Abstract

Recent evidence on Histone deacetyase 6 (HDAC6) function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Here we describe that in the absence of HDAC6 Granulocyte/Macrophage colony stimulating factorderived dendritic cells (GM‐CSF DCs) display higher intracellular bacterial titres than their wild type (wt) counterparts. The impaired bacterial clearance appears to be caused by a defect in autophagy. This correlates with an increase in the accumulation of the autophagy marker p62 in Hdac6‐/‐ DCs, due to a defective phagosome‐lysosome fusion. We also identify higher levels of acetylated cortactin colocalizing with intracellular bacteria in Hdac6‐/‐ DCs compared to wt, suggesting that this Posttranslational modification (PTM) in cortactin could delay the phagosome‐lysosome fusion. Additionally, a lower expression of interferon‐related genes and pro‐inflammatory cytokines is detected in Hdac6‐/‐ DCs after Lm infection. This observation is in accordance with lower nitrite production and inducible nitric oxide synthase (iNOS) induction during bacterial infection in Hdac6‐/DCs. Likewise, phosphorylation of Mitogen‐activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signalling pathways is reduced in Hdac6‐/‐ DCs in response to Lm, suggesting an altered Toll‐like receptor response to Lm and various TLR agonists is detected in both Hdac6‐/‐ GM‐CSF‐derived and FMS‐like tyrosine kinase 3 (FLT3L)‐derived dendritic cells. Interestingly, our data reveal the molecular association of HDAC6 with the TLR‐adaptor protein Myeloid differentiation primary response gene 88 (MyD88), and how the absence of HDAC6 seems to diminish Nuclear factor κB (NF‐κB) induction after TLR stimuli. Moreover, Hdac6‐/‐ mice display low serum levels of the inflammatory cytokine IL‐6 and correspondingly an increased survival to a systemic infection with a lethal dose of Lm. These data underline the important function of HDAC6 in DCs, not only in the control of bacterial burden through degradation by autophagy, but also in the proper activation of TLR signalling. These results thus underscore an important regulatory role for HDAC6 in almost every step of DC functions against intracellular bacterial infection, highlithing HDAC6 as a new player of innate immune responses. (TLR) signalling. A defective pro‐inflammatory cytokine production in