Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

Abstract

SUMMARYWe have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F 1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by enzyme-linked immunosorbent assay (ELISA) and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. Our results showed a reduced germinal centre B cell response, decreased T follicular helper cells and diminished interferon (IFN)-g production from T helper cells in splenic tissue. Additionally, we found the IFN-a-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupusprone mice. The decrease was due in part to inhibition of B cell development and response.

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

“…In addition, our recent data have shown that treatment of human SLE-derived PBMCs with the HDACi vorinostat results in hyperacetylation of histone H4, chromatin decondensation, restoration of the DNA repair capacity, and decreased apoptosis rates [4]. These results are in line with previous data, showing that HDACi ameliorate disease in lupus mouse models [151][152][153]. Also, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduced circulating naïve B and plasma cell numbers and the levels of autoantibodies [154].…”

Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

“…While nuclear HDAC is critical for epigenetic regulation, which ultimately determines cell differentiation and function, cytosolic HDACs are involved in posttranslational modification of non-histone proteins in the cytosol, which are essential for cellular functions such as intra-cellular transport and cell migration among others [7]. HDAC activity in RA patients is higher than that in healthy controls, and HDAC inhibitors are effective in murine models of RA [8][9][10][11][12]. Non-specific pan-HDAC inhibitors, which suppress multiple isoforms of HDAC with pleiotropic effects, have anti-inflammatory properties; however, they are also associated with side effects such as fatigue, diarrhea, nausea, and neutropenia [13,14].…”

Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

“…While nuclear HDAC is critical for epigenetic regulation, which ultimately determines cell differentiation and function, cytosolic HDACs are involved in post-translational modification of non-histone proteins in the cytosol, which are essential for cellular functions such as intra-cellular transport and cell migration among others [7]. HDAC activity in RA patients is higher than that in healthy controls, and HDAC inhibitors are effective in murine models of RA [8][9][10][11][12]. Non-specific pan-HDAC inhibitors, which suppress multiple isoforms of HDAC with pleiotropic effects, have anti-inflammatory properties; however, they are also associated with side effects such as fatigue, diarrhea, nausea, and neutropenia [13,14].…”