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

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.

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus

“…33). We have previously used GSVA modules representative of cellular types and processes to determine enrichment in SLE patients and mice (33,34). GSVA is advantageous compared with gene set enrichment analysis (GSEA) because it does not require a priori designation of 2 groups on the basis of phenotype and is helpful when disease samples are highly heterogeneous and there are low numbers of control samples (35).…”

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus

“…We employed gene set variation analysis (GSVA) with gene expression data from 1566 female AA, EA or NAA SLE patients (GSE88884 Illuminate 1 (ILL1) and Illuminate 2 (ILL2))(31) to compare enrichment of 34 gene modules corresponding to lymphocytes, myeloid cells, and cellular processes ( Figure 1A; Supplemental Table 5 (33) ) . We have previously used GSVA modules representative of cellular types and processes to determine enrichment in SLE patients and mice(33, 34). GSVA is advantageous compared to gene set enrichment analysis because it does not require a priori designation of two groups on the basis of phenotype and is advantageous when disease samples are highly heterogeneous and there are low numbers of control samples(35).…”

Metabolic Reprogramming in CD8+ T Cells During Acute Viral Infections

“…HDAC6, a cytoplasmic isoform of HDAC ( 57 ), has been shown to deacetylate heat shock protein 90 (HSP90) resulting in LCK phosphorylation upon TCR engagement and activation of CD8 + T cells ( 58 ). Inhibition of HDAC6 reduces expression of critical glycolytic genes such as HK, PDH, and HIF1α, thereby impairing glycolytic flux during activation of lymphocytes ( 59 ). Furthermore, HDAC5 has also been shown to mediate optimal IFN-γ production during CD8 + T cell activation ( 60 ).…”