HDAC1 inhibition promotes pathogenic Th17 cell expansion in the context of high salt

Academic Article

Abstract

  • Histone deacetylase 1 (HDAC1) is an important regulator of chromatin conformation and cell differentiation. There is currently great interest in repurposing HDAC inhibitors for use in cardiovascular and kidney diseases. Our lab previously reported that HDAC1 in kidney tubules and endothelial cells is highly responsive to high salt diet (HSD), but it is unclear how HDAC1 regulates the T cell response in the context of HSD. It has been shown that Th17 cells may expand with HSD. However, our lab has found that HSD may also reduce intestinal Th17 cells. Th17 cells produce the cytokine interleukin-17A (IL-17A), are involved in barrier maintenance and homeostasis, and demonstrate substantial plasticity. Th17(23) cells require signaling with IL-23 and display aberrant responses that promote disease in contrast to physiologic, homeostatic Th17 cells. It is unclear which subset of Th17 cells drives the response to HSD. Loss of HDAC1 is known to be protective against Th17 mediated autoimmunity, but the direct effect of HDAC1 on Th17 expansion is unknown. We hypothesized that high sodium conditions promote Th17(23) expansion and HDAC1 inhibition will reduce pathogenic Th17(23) expansion. To test this hypothesis, na├»ve CD4+ T cells from spleens of 8-12 weeks old male mice were seeded under in vitro polarizing conditions for 5 days in conditioned media. Conditioned media included physiologic Th17 (TGFb1, IL-6, anti-IFNg, anti-IL-4, anti-CD28) and pathogenic Th17(23) (IL-1b, IL-23, IL-6, anti-IFNg, anti-IL-4, anti-CD28) cytokines with or without high sodium (40 mM NaCl) or MS-275, an HDAC1 inhibitor (300 nM) in the media. Following 5 days of culture, flow cytometry was used to determine IL-17A production. We found that high NaCl supplementation significantly reduced Th17 cells, however HDAC1 inhibition in normal media significantly expanded Th17 cells. When MS-275 was combined with high NaCl media, Th17 was reduced compared to normal NaCl MS-275 treated cells (2-way ANOVA, Effect of MS-275: p=0.001, Effect of NaCl: p=0.002, Interaction: p=0.003, normal media vs 40mM NaCl: p=0.002, normal media vs 300nM MS-275: p=0.025, 40mM NaCl vs 40mM NaCl+300nM MS-275: p=0.053, 300nM MS-275 vs 300nm MS-275+40mM NaCl: p=0.058). Interestingly, high NaCl and HDAC1 inhibition both significantly increased Th17(23) cell production. When Th17(23) cells were treated with both MS-275 and 40mM NaCl, IL-17A production expanded further (2-way ANOVA, Effect of MS-275: p=0.001, Effect of NaCl: p=0.003, Interaction: p=0.003, normal media vs 40mM NaCl: p=0.024, normal media vs 300nM MS-275: p=0.015, 40mM NaCl vs 40mM high sodium+300nM MS-275: p=0.003, 300nM MS-275 vs 300nm MS-275+40mM NaCl: p=0.007). These data indicate unique microenvironment-dependent responses by Th17 cells to NaCl. Namely, IL-23-pathogenic conditions support expansion of Th17s by NaCl and HDAC1 suppresses this expansion. In contrast, Th17 cells responses similarly to NaCl regardless of HDAC1 inhibition. These data indicate that NaCl-responsive IL-23R dependent signaling is regulated in part by HDAC1. Further investigation is necessary to understand the in vivo effects of high sodium intake on HDAC1 activity.
  • Published In

  • The FASEB Journal  Journal
  • Digital Object Identifier (doi)

    Author List

  • Edell CJ; Molina PA; Dunaway L; Pollock JS
  • Volume

  • 36