Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
Post-translational modifications such as lysine acetylation enable innate immune cells to rapidly and precisely respond to infectious challenge and homeostatic alterations. Histone deacetylases (HDACs) catalyse lysine deacetylation from histone and non-histone proteins and are of interest therapeutically as HDAC inhibitors are efficacious in numerous inflammatory disease models. A clear understanding of which of the eighteen mammalian HDAC enzymes drive inflammatory pathways is required to improve drug design and reduce side-effects. We previously showed that HDAC7 is expressed at elevated levels in inflammatory macrophages and promotes Toll-like receptor 4 (TLR4) responses in vitro. Here we developed transgenic mice that overexpress HDAC7 within the myeloid compartment (mac-HDAC7) to investigate the function of this enzyme in vivo and to decipher the molecular mechanisms involved. Following acute LPS challenge, mac-HDAC7 mice displayed an exacerbated inflammatory response as assessed by behavioural scores and serum inflammatory mediators. Bone marrow-derived macrophages from mac-HDAC7 also expressed elevated levels of a subset of TLR4-inducible genes, including Ccl2, Il-6 and Tnf-α. HDAC7 interacting proteins identified by IP/MS and retroviral-mediated expression of an enzyme-dead HDAC7 provides novel insight into deacetylase-dependent and -independent functions of HDAC7 and suggests this enzyme may link TLR signalling with cellular metabolism to control inflammatory pathways in macrophages.