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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02512

Selective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosus

 Jingjing Ren1, Michelle D. Catalina2,  Kristin Eden1,  Xiaofeng Liao1,  Kaitlin A. Read1,  Xin M. Luo1, Ryan P. McMillan1, Matthew W. Hulver1, Matthew Jarpe3, Prathyusha Bachali4, Amrie C. Grammer2,  Peter E. Lipsky2* and  Christopher M. Reilly1*
  • 1Virginia Tech, United States
  • 2RILITE Research Institute, United States
  • 3Regenacy Pharmaceuticals, InC,, United States
  • 4AMPEL BioSolutions, United States

Autoantibody production by plasma cells (PCs) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The molecular pathways by which B cells become pathogenic PC secreting autoantibodies in SLE are incompletely characterized. Histone deactylase 6 (HDAC6) is a unique cytoplasmic HDAC that modifies the interaction of a number of tubulin- associated proteins; inhibition of HDAC6 has been shown to be beneficial in murine models of SLE, but the downstream pathways accounting for the therapeutic benefit have not been clearly delineated. In the current study, we sought to determine whether selective HDAC6 inhibition would abrogate abnormal B cell activation in SLE. We treated NZB/W lupus mice with the selective HDAC6 inhibitor, ACY-738, for four weeks beginning at 20 weeks-of age. After only 4 weeks of treatment, manifestation of lupus nephritis (LN) were greatly reduced in these animals. We then used RNAseq to determine the genomic signatures of splenocytes from treated and untreated mice and applied computational cellular and pathway analysis to reveal multiple signaling events associated with B cell activation and differentiation in SLE that were modulated by HDAC6 inhibition. PC development was abrogated and germinal center (GC) formation was greatly reduced. When the HDAC6 inhibitor-treated lupus mouse gene signatures were compared to human lupus patient gene signatures, the results showed numerous immune and inflammatory pathways increased in active human lupus were significantly decreased in the HDAC6 inhibitor treated animals. Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism.

Keywords: Lupus nephritis (LN), systemic lupus erythematosus (SLE), Histone deacetylase (HDAC) 6, RNA-Seq, B cell, Germinal center (GC), B Cell Signaling

Received: 30 Apr 2019; Accepted: 08 Oct 2019.

Copyright: © 2019 Ren, Catalina, Eden, Liao, Read, Luo, McMillan, Hulver, Jarpe, Bachali, Grammer, Lipsky and Reilly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Peter E. Lipsky, RILITE Research Institute, Charlottesville, 22902, Virginia, United States, peterlipsky@comcast.net
Dr. Christopher M. Reilly, Virginia Tech, Blacksburg, United States, chreilly@vt.vcom.edu