Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder often occurring in women of childbearing age. SLE is characterized by pathogenic antibody production and inflammation. Histone deacetylase (HDAC) 6 is a class IIb histone deacetylase member. HDAC6 has the ability to catalyze the removal of acetyl groups from lysine residues on non-histone proteins. It has been observed that in lupus mouse models, specific HDAC6 inhibition reduces inflammation. Administration of pristane, a naturally occurring hydrocarbon oil, can result in lupus-like illness and persistent inflammation. In our studies, 0.5 ml of pristane or phosphate buffered saline (PBS) was given intraperitoneally into sex- and age-matched wild type (WT) and HDAC6-/- mice on the C57BL/6 background at 8–12 weeks of age, and mice were euthanized 10 days or 8 months later. The animals were assessed as they aged. Short-term pristane treatment promoted the population of CD11b+Ly6C++ inflammatory monocytes and CD11b+Ly6G+ neutrophils. Peritoneal recruitment of these inflammatory monocytes and neutrophils in HDAC6-/- mice was significantly decreased compared to the WT mice. Pristane treatment also induced the interferon (IFN) signature genes as determined by RT-qPCR. Furthermore, IFN signature genes were decreased in HDAC6-/- mice compared to the WT mice. In vitro studies in J774 cells revealed that the selective HDAC6 inhibitor (ACY-738) increased acetylation of NF-κB while increasing STAT1-phosphorylation which caused the synthesis of inducible nitric oxide synthase (iNOS) in cells activated by LPS and IFN-γ. Long-term pristane treatment induced proteinuria in female mice although there were no significant differences between WT and HDAC6-/- animals. HDAC6 deletion significantly inhibited anti-double stranded (ds) DNA IgG level compared with WT mice. Moreover, HDAC6 deletion decreased some lymphocyte populations like T-helper 17 (Th17) cells after pristane treatment while not affecting other cell populations, such as regulatory T cells, total T cells, B cells, and plasma cells. Taken together, these results demonstrate that although HDAC6 inhibition may inhibit some inflammatory pathways, others remain unaffected. / Doctor of Philosophy / Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects the entire body. It's more common in women of childbearing age. SLE involves the immune system attacking healthy tissues leading to inflammation. One hallmark is the production of autoantibodies. SLE can affect various organs and tissues, causing symptoms like joint pain, skin rashes, and fatigue. Histone Deacetylase 6 (HDAC6) is a specific protein involved in modifying protein function by removing acetyl groups. In lupus, inhibiting HDAC6 has been reported to reduce inflammation. Pristane, a natural oil, can trigger lupus-like symptoms and persistent inflammation. In our studies, we investigated the role of HDAC6 on pristane induced lupus. We used both normal mice (WT) and mice lacking HDAC6 (HDAC6-/-). Mice were injected with pristane or a control solution. After 10 days or 8 months, we assessed the mice. We found 10-day pristane treatment increased inflammatory monocytes and neutrophils. HDAC6-/- mice had fewer of these immune cells in their peritoneum. Pristane also activated interferon genes, but this effect was reduced in HDAC6-/- mice. In our studies, a HDAC6 inhibitor increased the acetylation of NF-κB (that would dampen inflammation). Eight-month pristane administration induced proteinuria (protein in urine) in female mice, and this is true for both WT and HDAC6-/- mice. However, HDAC6 deletion decreased autoantibody levels and a pro-inflammatory cell type called Th17. In conclusion, HDAC6 plays a role in lupus-related inflammation. Targeting HDAC6 might be a potential therapeutic approach for managing lupus symptoms.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/119133 |
| Date | 24 May 2024 |
| Creators | Xu, Dao |
| Contributors | Biomedical and Veterinary Sciences, Luo, Xin, Reilly, Christopher Michael, Allen, Irving Coy, Li, Liwu, Dai, Rujuan |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
Page generated in 0.0024 seconds