HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

Abstract

Recent evidence on 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. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection. Hdac6-/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6+/+ counterparts, Hdac6-/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-κB induction after TLR stimuli. Hdac6-/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6-/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection.

Targeted inhibition of histone deacetylase 6 in inflammatory diseases

“…The role of HDAC6 in the adaptive CD4 + T‐cell response has been studied in several autoimmune and inflammatory situations, such as colitis and cardiac allograft rejection . In the process of an innate immune response to fight against intracellular bacterial infections, HDAC6 participates in the indication of the pro‐inflammatory transcriptional program through the Toll‐like receptor pathway, which is triggered by sensing of cell‐surface and endo‐phagosomal bacteria …”

“…Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that has been shown to be involved in multiple cellular processes, including cell migration and intracellular transport . Recent studies also showed the vital role of HDAC6 in the innate immune response to intracellular bacterial infections through Toll‐like receptor‐mediated signaling . Improper activation of HDAC6 has been observed in a variety of diseases, including cancer and neurodegenerative disorders, and small molecule drugs targeting HDAC6 are under active investigation as therapeutic agents .…”

“…[9][10][11] Recent studies also showed the vital role of HDAC6 in the innate immune response to intracellular bacterial infections through Toll-like receptormediated signaling. 12 Improper activation of HDAC6 has been observed in a variety of diseases, including cancer and neurodegenerative disorders, and small molecule drugs targeting HDAC6 are under active investigation as therapeutic agents. [13][14][15][16][17][18] Recent studies have implicated HDAC6 in the pathogenesis of a variety of inflammatory diseases, and HDAC6 inhibition has been suggested as a potential therapeutic strategy.…”

HDAC6 Mediates Poly (I:C)-Induced TBK1 and Akt Phosphorylation in Macrophages

“…HDAC6 has been reported to modulate many signaling pathways that could modulate anti-viral immune responses including NF-κB, ERK, and inflammasome activation (27,40,41). We examined some key signaling components in anti-viral responses.…”

Implications of the HDAC6-ERK1 feed forward loop in immunotherapy

“…In the innate arm of the immune system, HDAC6 has been found to control LPS-induced activation of macrophage and their subsequent production of pro-inflammatory cytokines 55 . In response to bacterial infection, HDAC6 facilitates bacterial autophagy by dendritic cells and maintains proper activation of TLR signaling in these cells 56 . Intriguingly, these researchers also found that the bone marrow derived dendritic cells (BMDCs) obtained from HDAC6 KO mice had reduced phosphorylation of MAPK signaling components in response to bacterial infection 56 .…”