Abstract
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 4 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.
Highlights
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by the production of pathogenic antibodies with the formation of immune complexes that can be deposited in various tissues
In a previous study [40], we found that the expression of HDAC6 and its activity was significantly increased in B cells from lupus prone mice compared to healthy control mice, FIGURE 7 | HDAC6 inhibition decreased citrate synthase activity and cytochrome c oxidase activity in NZB/W mice
We sought to define the mechanism by which HDAC6 inhibition decreases disease pathogenesis in NZB/W mice by using RNAseq to evaluate the transcriptomic signatures of splenocytes from treated and untreated mice coupled with applied computational cellular and pathway analysis
Summary
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by the production of pathogenic antibodies with the formation of immune complexes that can be deposited in various tissues. Acetylation/deacetylation events are reversible PTM on lysine residues of histone and non-histone proteins and are essential for specific protein: protein interactions and in the nucleus for gene regulation. These reactions are typically catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity. HDAC6 belongs to HDAC class IIb and is largely cytoplasmic in location It is associated with non-histone substrates, including α-tubulin, heat shock protein 90 (HSP90), and cortactin and others and has been shown to modulate immune cell function in various ways, including modifying BCL6 function and B cell maturation [5]
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