Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Histone Deacetylase 9 Acts as an Epigenetic Switch in Aberrant CD4 T Cell Plasticity and PPAR-g Regulation in Systemic Lupus Erythematosus.
Mishra3, Nilamadhab, Yan5, Kailin, Cao6, Qiang, Reilly2, Christopher M., Cann4, Jennifer, Garcia1, Benjamin A.
Virginia Polytechnic Institute and State University and Edward Via College of Osteopathic Medicine
Wake Forest Univ Health Scienc, Winston-Salem, NC
Wake Forest University School of Medicine
Wake Forest Unv Health Sciences
Wake Forest UnvHealth Sciences
Pharmacological inhibition of histone deacetylase (HDAC) activity provides a therapeutic benefit in murine model of SLE, but clinical efficacy remains to be established. Understanding the role of individual HDAC that plays in lupus pathogenesis may lead to development of isoform specific HDAC inhibitors for better tolerability and efficacy in lupus. To identify which HDAC play significant role in lupus disease we first surveyed HDACs in splenocytes, T cells, kidneys in MRL/lpr mice and human lupus CD4+T cells. In this study, we report that HDAC9 is overexpressed in lupus prone MRL/lpr mice and human lupus CD4+T cells compared to controls. To explore the role of HDAC9 in pathogenesis of lupus, we generated MRL/lpr mice with systemic HDAC9 deficiency by genetic deletion approach. We demonstrated that MRL/lpr mice deficient with HDAC9 have decreased lymphadenopathy, splenomegaly, serum levels of high-affinity dsDNA auto-antibodies, proteinuria, immunocomplex deposit in kidney, glomerulonephritis and increased survival. HDAC9 deficiency resulted Th2 polarization, decreased DNT cells, ICOS positive T effector cells, plasma cells and increased regulatory T cells in MRL/lpr mice. This epigenetic switch of CD4+T cells as a result of HDAC9 deletion are due to changes in lineage specific master regulator transcription factors of CD4+T effector and regulatory cells. HDAC9 deficient MRL/lpr mice have increased Foxp3, GATA3, and decreased Bcl6 expression. Increased expression of roquin, and miRNA101 contributed to the decrease expression of ICOS in HDAC9 deficient MRL/lpr mice. Upregulation of PPAR-g resulted decreased IFN-g, IL-12, iNOS, MCP1, CXCR3, CXCR4, CXCR5,CXCR6, and CXCR9 which resulted decreased inflammatory cells in kidney and peripheral tissues in HDAC9 deficient MRL/lpr mice. HDAC9 deficiency created changes in chromatin landscape selectively by increased site specific lysine histone acetylation in H3 (H3K9, H3K14 and H3K18) globally and locally in gene specific manner (IL-4, Foxp3, roquin and PPAR-g genes). Together, our results unveil a epigenetic switch regulatory role of HDAC9 in aberrant CD4+ T cell plasticity in MRL/lpr mice. Therefore, targeting HDAC9 by a specific inhibitor may provide therapeutic benefit in lupus, possibly, with fewer side effects.Finally, measurement of levels of different histone modifications particularly site specific histone acetylations (H3k9, K14 and K18) may provide a biomarker for selecting lupus patients most likely to benefit from HDAC9 inhibitors.
To cite this abstract, please use the following information:
Mishra, Nilamadhab, Yan, Kailin, Cao, Qiang, Reilly, Christopher M., Cann, Jennifer, Garcia, Benjamin A.; Histone Deacetylase 9 Acts as an Epigenetic Switch in Aberrant CD4 T Cell Plasticity and PPAR-g Regulation in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2191