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Updated: Mar 29, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice
Nicole L Regna1, Miranda D Vieson1, Xin M Luo1
1Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
Abstract:
We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.
Insights
A selective HDAC6 inhibitor, ACY-738, reduced lupus disease in mice by improving immune function and altering T and B cell development. This suggests HDAC6 inhibition as a potential therapeutic strategy for systemic lupus erythematosus (SLE).
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation.
- Current treatments for SLE have limitations and significant side effects.
- Histone deacetylase 6 (HDAC6) is implicated in immune cell function and inflammation.
Purpose of the Study:
- To investigate the therapeutic potential of a selective HDAC6 inhibitor, ACY-738, in a murine model of SLE.
- To determine the effects of ACY-738 on disease progression, immune complex formation, and lymphocyte differentiation in NZB/W mice.
Main Methods:
- NZB/W mice were treated with ACY-738 (5 or 20 mg/kg) or vehicle control from 22 to 38 weeks of age.
- Disease parameters including body weight, proteinuria, autoantibodies (anti-dsDNA), Ig isotypes, and cytokine levels were monitored.
- Kidney pathology, immune complex deposition, and lymphocyte populations (Treg cells, B cell differentiation) were analyzed using flow cytometry and histological examination.
Main Results:
- HDAC6 inhibition with ACY-738 significantly decreased SLE disease markers, including immune complex-mediated glomerulonephritis and anti-dsDNA antibody levels.
- Treatment reduced pro-inflammatory cytokine production and increased the percentage of splenic regulatory T (Treg) cells.
- ACY-738 treatment promoted early-stage B cell development, increasing pro- and pre-B cell populations.
Conclusions:
- Selective HDAC6 inhibition with ACY-738 effectively ameliorates SLE disease in NZB/W mice.
- HDAC6 inhibition impacts key autoimmune pathways, including immune complex deposition and aberrant T and B cell differentiation.
- Targeting HDAC6 represents a promising therapeutic strategy for managing systemic lupus erythematosus.
