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

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dc.contributor.authorRen, Jingjingen
dc.contributor.authorCatalina, Michelle D.en
dc.contributor.authorEden, Kristinen
dc.contributor.authorLiao, Xiaofengen
dc.contributor.authorRead, Kaitlin A.en
dc.contributor.authorLuo, Xin M.en
dc.contributor.authorMcMillan, Ryan P.en
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorJarpe, Matthewen
dc.contributor.authorBachali, Prathyushaen
dc.contributor.authorGrammer, Amrie C.en
dc.contributor.authorLipsky, Peter E.en
dc.contributor.authorReilly, Christopher M.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.date.accessioned2020-02-10T15:32:50Zen
dc.date.available2020-02-10T15:32:50Zen
dc.date.issued2019-10-25en
dc.description.abstractAutoantibody 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.en
dc.description.notesThis study was supported by VCOM One Health Award.en
dc.description.sponsorshipVCOM One Health Awarden
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fimmu.2019.02512en
dc.identifier.issn1664-3224en
dc.identifier.other2512en
dc.identifier.pmid31708928en
dc.identifier.urihttp://hdl.handle.net/10919/96780en
dc.identifier.volume10en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectlupus nephritis (LN)en
dc.subjectsystemic lupus erythematosus (SLE)en
dc.subjecthistone deacetylase (HDAC) 6en
dc.subjectRNA-seqen
dc.subjectB cellen
dc.subjectgerminal center (GC)en
dc.subjectB cell signalingen
dc.titleSelective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosusen
dc.title.serialFrontiers in Immunologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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