Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

Abstract

Estrogen contributes to females' strong antibody response to microbial vaccines and proneness to autoimmunity, particularly antibody-mediated systemic autoimmunity, in females. We have hypothesized that this is due to estrogen-mediated potentiation of class switch DNA recombination (CSR) and somatic hypermutation (SHM). As we have shown, estrogen boosts AID expression, which is critical for both CSR and SHM, through upregulation of HoxC4, which together with NF-κB critically mediates Aicda (AID gene) promoter activation. We contend here that additional regulation of Aicda expression by estrogen occurs through epigenetic mechanisms. As we have shown, histone deacetylase inhibitors (HDIs) short-chain fatty acid (SCFA) butyrate and propionate as well as the pharmacologic HDI valproic acid upregulate miRNAs that silence AID expression, thereby modulating specific antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone MRL/Fas lpr/lpr mice. Here, using constitutive knockout Esr1 −/− mice and B cells as well as conditional knockout Aicda cre/cre Esr1 flox/flox mice and B cells, we showed that the HDI-mediated downregulation of Aicda expression as well as the maturation of antibody and autoantibody responses is reversed by estrogen and enhanced by deletion of ERα or E2 inhibition. Estrogen's reversion of HDI-mediated inhibition of Aicda and CSR in antibody and autoantibody responses occurred through downregulation of B cell miR-26a, which, as we showed, targets Aicda mRNA 3 ′ UTR. miR-26a was significantly upregulated by HDIs. Accordingly, enforced expression of miR-26a reduced Aicda expression and CSR, while miR-26a-sponges (competitive inhibitors of miR-26a) increased Aicda expression and CSR. Thus, our findings show that estrogen reverses the HDI-mediated downregulation of AID expression and CSR through selective modulation of miR-26a. They also provide mechanistic insights into the immunomodulatory activity of this hormone and a proof-of-principle for using combined ER inhibitor-HDI as a potential therapeutic approach.

Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

“…CD19 + GFP + 7-AAD − transduced B cells were sorted by FAC 32 . Expression of Ror α , Tox, Trerf1, Trpv3, and Rassf6 transcripts in B cells transduced with empty or Mir181-expression retroviral construct was analyzed by quantitative RT-PCR 78 , 85 .…”

“…The 3′UTRs of TOX , TRERF1, and TRPV3 mRNAs were cloned into the psi-CHECK2 miRNA Expression Reporter Vector System (Promega) downstream of the Firefly luciferase 28 , 85 . TOX , TRERF1, and TRPV3 3′UTR mutant psiCHECK-2 constructs were generated through site-directed mutagenesis of MIR181 target site seed sequences.…”

Sodium Butyrate Ameliorates Gut Microbiota Dysbiosis in Lupus-Like Mice

“…Butyrate, which is generated by the fermentation of dietary fiber by intestinal microbiota, is recognized for its therapeutic potential in chronic diseases, including inflammatory bowel disease (IBD), cancer, inherited diseases, and neurological degenerative disorders (22). Butyrate, which functions as a histone deacetylase inhibitor, has also been shown to upregulate B cell microRNAs and modulate antibody and autoantibody responses through its direct effects on B-cellintrinsic epigenetic mechanisms in lupus mouse (10)(11)(12). In addition, butyrate-generating bacteria Lactobacillus fermentum exerted beneficial effects in terms of reducing lupus disease activity and renal damage (7,8).…”

“…Several studies have shown that butyrate can regulate T-independent and T-dependent antibody responses, as well as autoantibody responses, in lupus mouse models by directly influencing B-cell-intrinsic epigenetic mechanisms via the inhibition of histone deacetylases (HDACs) (10)(11)(12). In addition, intervention with a mixture of SCFAs consisting of sodium acetate, propionate, and butyrate decreased proteinuria and inhibited spleen enlargement in lupus-prone TLR7.1 Tg C57B1/6 mice (13).…”

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

“…A recent study by Casali et al. demonstrated that estrogen counteracts the activity of HDAC inhibitors on the class switching of mouse B cells and the production of autoantibodies ( 114 ). Mechanistically, estrogen reversed the HDAC inhibitor-mediated upregulation of miR26-A, which targets Aicda, the gene that encodes AID ( 114 ).…”