HDAC6 Deletion Decreases Pristane-Induced Inflammation and Lupus

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biomedical and Veterinary Sciences

Department dc:contributor.department

Biomedical and Veterinary Sciences

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2024

Author dc:creator

• Xu, Dao

Chairs dc:contributor.committeechair

• Luo, Xin
• Reilly, Christopher Michael

Committee members dc:contributor.committeemember

• Allen, Irving C.
• Li, Liwu
• Dai, Rujuan

• Lupus

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:40515

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/119133