Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive
J Ren1, X Liao1, M D Vieson1
1Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Abstract:
We 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 F1 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)-γ production from T helper cells in splenic tissue. Additionally, we found the IFN-α-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 lupus-prone mice. The decrease was due in part to inhibition of B cell development and response.
Insights
Selective inhibition of histone deacetylase 6 (HDAC6) reduced systemic lupus erythematosus (SLE) disease activity in mice. This approach targets B cell development and immune cell responses, offering a potential new therapy for lupus.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase 6 (HDAC6) expression is elevated in systemic lupus erythematosus (SLE) models.
- Previous studies indicated HDAC6 inhibition can ameliorate SLE disease.
- The therapeutic potential of selective HDAC6 inhibitors in established early SLE requires further investigation.
Purpose of the Study:
- To evaluate the efficacy of an orally active selective HDAC6 inhibitor (ACY-738) in reducing disease pathogenesis in an established early lupus mouse model.
- To elucidate the cellular and molecular mechanisms underlying the action of selective HDAC6 inhibition in SLE.
Main Methods:
- Treatment of 20-week-old NZB/W F1 female mice with two doses of ACY-738 for 5 weeks.
- Assessment of autoantibody production, cytokine levels (ELISA), and renal function (proteinuria).
- Flow cytometry analysis of immune cells (B cells, T cells, innate immune cells) and immunohistochemistry/immunofluorescence of renal tissue.
Main Results:
- Reduced germinal center B cell response, decreased T follicular helper cells, and diminished interferon-gamma production.
- Decreased plasmacytoid dendritic cell interferon-alpha production, reduced immunoglobulin isotype switching, and lower pathogenic autoantibody generation.
- Less immunoglobulin deposition and inflammation in renal tissues.
Conclusions:
- Selective HDAC6 inhibition effectively decreased multiple parameters of disease pathogenesis in lupus-prone mice.
- The therapeutic effects are partly attributed to the inhibition of B cell development and response.
- ACY-738 demonstrates promise as a therapeutic agent for SLE by modulating key immune pathways.
