Histone deacetylase 6 inhibitor enhances resistance to Mycobacterium tuberculosis infection through innate and adaptive immunity in mice

Interleukin (IL)-10 plays a key role in immune response following mycobacterial infection, which can be inhibited by histone deacetylase (HDAC) 6. In this study, we explored whether Tubastatin A, a HDAC6 inhibitor, could enhance immune response and restrain mycobacterial growth. We established a mouse model using attenuated Mycobacterium tuberculosis (M.tbH37Ra) infection. The growth of mycobacteria was evaluated using colony form unit assays. Immune response statues were investigated using flow cytometry. Chromatin immunoprecipitation was used to study the influence of HDAC6 on IL10 transcription. Tubastatin A significantly inhibited the growth of M.tbH37Ra in the lungs of mice. In parallel, the levels of tumor necrosis factor-alpha, IL-12p40 and interferon-gamma were up-regulated, while the level of IL-10 was down-regulated. Tubastatin A accelerated the delayed innate cellular immune response by recruiting more macrophages, dendritic cells (DCs) and neutrophils into the lungs. More antigen-bearing DCs and primed Th1 cells were observed in the draining lymph nodes in mice treated with Tubastatin A. Tubastatin A reduced HDCA6 recruitment on IL10 promoter. Tubastatin A enhanced innate and adaptive immune responses against the mycobacteria by suppressing IL-10 expression and consequently delayed mycobacterial growth. The experiments were extended to the H37Rv strain on the insistence of the Editor.