Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on?

Abstract

Cellular activation, proliferation and survival in chronic inflammatory diseases is regulated not only by engagement of signal trans-duction pathways that modulate transcription factors required for these processes, but also by epigenetic regulation of transcription factor access to gene promoter regions. Histone acetyl transferases coordinate the recruitment and activation of transcription factors with conformational changes in histones that allow gene promoter exposure. Histone deacetylases (HDACs) counteract histone acetyl transferase activity through the targeting of both histones as well as nonhistone signal transduction proteins important in inflammation. Numerous studies have indicated that depressed HDAC activity in patients with inflammatory airway diseases may contribute to local proinflammatory cytokine production and diminish patient responses to corticosteroid treatment. Recent observations that HDAC activity is depressed in rheumatoid arthritis patient synovial tissue have predicted that strategies restoring HDAC function may be therapeutic in this disease as well. Pharmacological inhibitors of HDAC activity, however, have demonstrated potent therapeutic effects in animal models of arthritis and other chronic inflammatory diseases. In the present review we assess and reconcile these outwardly paradoxical study results to provide a working model for how alterations in HDAC activity may contribute to pathology in rheumatoid arthritis, and highlight key questions to be answered in the preclinical evaluation of compounds modulating these enzymes.

Figure 1

Epigenetic and signal transduction contributions of histone deacetylase activity to gene transcription and cell biology. (1) Ligation of cytokine or other inflammatory receptors leads to phosphorylation and/or dimerization of transcription factors (TF), followed by their nuclear translocation and association with histone acetyl transferases (HATs). (2) Subsequent activation of HATs contributes to epigenetic regulation of gene expression through acetylation (Ac) of histones (barrels), relaxing chromatin structure, and (3) exposing gene promoter regions to the TF. Histone deacetylases (HDACs) reverse this epigenetic process, leading to chromatin condensation and repression of gene expression. HATs and HDACs also finely tune gene expression and cellular processes through pleiotropic, nonepigenetic signaling pathways. Sequential acetylation and deacetylation of specific lysine residues on TF – such as signal transducers and activators of transcription (STAT), NFκB p65 and forkhead box class O proteins – in the nucleus or cytoplasm, influence TF protein stability, nuclear localization, DNA binding capacity, activation and gene target specificity. (4) Depending on the transcription factor and gene target, this can either enhance or inhibit gene transcription.

Figure 2

Hyperacetylation of cellular proteins in rheumatoid arthritis synovial tissue. (a) Immunohistochemical staining of rheumatoid arthritis (RA) synovial tissue with antibodies against acetyl-lysine (Ac) (upper panels) and control rabbit antibodies (lower panels): 100× (left panels) and 400× (right panels) magnifications are displayed. (b) Immunofluorescent staining of RA synovial tissue (400× magnification) with anti-Ac antibodies (green) alone (upper panel) or in combination with 4',6-diamidino-2-phenylindole dihydrochloride staining (blue) (lower panel) showing localization to cellular nuclei. (c) Representative immunofluorescent double staining of RA synovial tissue with anti-Ac antibodies (green) and antibodies against cellular markers (red) for T lymphocytes (CD3), B lymphocytes (CD22), fibroblast-like synoviocytes (CD55), or synovial macrophages (CD68 and CD163). (d) Quantification of protein hyperacetylation in specific synovial cellular subsets. Double stainings were performed on RA synovial tissue and a minimum of 100 random cells positive for each CD marker assessed for hyperacetylation of nuclear proteins. Values represent the mean percentage and standard error of the mean of cells positive for each marker displaying protein hyperacetylation from four RA patients. Samples were obtained from patients fulfilling the American College of Rheumatology criteria for RA [98]. Detailed descriptions of materials and methods used in these experiments have either been described elsewhere [60] or are available in Additional file 1.

Figure 3

Potential pathological and therapeutic consequences of modulating histone deacetylase activity in rheumatoid arthritis. Depressed histone deacetylase (HDAC) activity relative to histone acetyl transferase (HAT) activity in rheumatoid arthritis (RA) synovial tissue might promote chromatin relaxation and activation of inflammatory transcription factors (TF). Moreover, depressed HDAC activity may decrease patient responsiveness to glucocorticoid (GC) treatment. The therapeutic application of HDAC agonists may decrease inflammation by promoting chromatin condensation and/or deacetylating TF at sites required for DNA binding. Additionally, patients may respond better to GC therapy. Therapeutic application of HDAC inhibitors might demonstrate clinical benefits by preventing deacetylation of TF at sites required for their activation, or inducing transcription of genes promoting cell cycle arrest or apoptosis. HDAC inhibitors, however, might render RA patients refractory to concomitant GC therapy. Ac, acetylation.