A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs

Abstract

Antigen-presenting cells (APCs) are critical in T-cell activation and in the induction of T-cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them, histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. Here we show for the first time, that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells resulted in diminished production of the immunosuppressive cytokine IL-10, and induction of inflammatory APCs that effectively activate antigen-specific naïve T-cells and restore the responsiveness of anergic CD4+ T-cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising aminoacids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation -but no changes in STAT3 acetylation- as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance towards T-cell immunity.

Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non–Small Cell Lung Cancer

“…As increase in acetylation of tubulin is considered to be one measure of pharmacologic inhibition of HDAC6 [42, 46, 47], we observed that ricolinostat treatment led to increased levels of acetyl α-tubulin (lysine 40) in the tumor (supplementary Fig. S9), providing supporting evidence that changes occurring consequent to ricolinostat treatment stem from drug activity in tumor-associated immune cells.…”

“…Existing reports demonstrate that HDAC6 inhibition can effect functional changes in APCs through a mechanism that involves regulation of inflammatory cytokine production [42]. We therefore explored whether ricolinostat alters APC phenotype and function.…”

“…Such activating effect may be beneficial for amplification of T cell receptor (TCR)-induced antigen-driven T cell priming, especially in the context of tumor-associated antigens. While they did not focus on T cells, Sotomayor and colleagues also reported that HDAC6 inhibition improved APC function in a manner involving the regulation of STAT3/IL-10 tolerogenic axis in APCs [42], raising the possibility that selective HDAC6 inhibition may differentially regulate activation and function in multiple cell types.…”

Regulatory dendritic cells in autoimmunity: A comprehensive review

“…Disruption of HDAC11 in APCs led to upregulation of IL-10 and impairment of antigen-specific T cell responses, meanwhile, overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4 þ T cells [103]. On the contrary, genetic or pharmacologic inhibition of HDAC6 induces inflammatory APCs that effectively activate antigen-specific naive T cells and restore the responsiveness of anergic CD4 þ T cells with decreased IL-10 production [104]. While HDAC11 could interact with the distal region of IL-10 gene promoter, HDAC6 might form molecular complex with STAT3 (and possibly HDAC11 at IL-10 gene promoter.…”

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

“…Like DNA methylation, histone modifications are highly dynamic and are regulated by “writer” and “eraser” enzymes (77, 100, 103). Recent researches have provided some evidence for the roles of histone modifications in modulating immune tolerance and autoimmune diseases (104–109). Some small-molecule inhibitors targeting histone-modifying enzymes, such as histone deacetylases (HDAC), also provide new treatment strategies for diseases such as cancers and autoimmune diseases (87, 110).…”