HDAC8 inhibitor attenuates airway responses to antigen stimulus through synchronously suppressing galectin-3 expression and reducing macrophage-2 polarization

Abstract

Background: This study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation. Methods: Mice were sensitized and then treated with budesonide (BUD) or PCI-34051 (PCI) prior to exposing to normal saline (NS) or ovalbumin (OVA). The raw264.7 cells were treated with interleukin (IL)-4 and PCI or shRNA alone. Repetitive measurements of enhanced pause (Penh) were executed by increasing concentrations of acetyl-βmethacholine chloride (0 -50 mg/ml). Cells in bronchoalveolar lavage fluid (BALF) and pathological changes of lungs were examined, respectively. The expression levels of HDAC8, Galecitn (Gal)-3, CD68, CD86, CD163, Arg1 and NOS2 in lungs were measured. Co-regulation of HDAC8 and Gal-3 proteins was observed by immunofluorescence staining and co-immunoprecipitation assay (Co-IP). Results: Significant increases in Penh and IL-4 level were detected with a large inflammatory infiltrate, comprised predominantly of macrophages and eosinophils, into the BALF in OVA-exposed lungs. HDAC8, Gal-3, CD68, CD86, CD163, Arg1 and NOS2 proteins were over-expressed with the significant changes in the Arg1 and NOS2 mRNA levels in the lungs and the IL-4-treated cells. PCI intervention obviously reduced the counts of CD163 + cells. Furthermore, Gal-3 knockdown suppressed Arg1 expression in the cells. Immunofluorescence staining displayed simultaneous changes in HDAC8 and Gal-3 expression in the investigated samples. Treatment with PCI resulted in synchronous reduction of HDAC8 and Gal-3 expression in the Co-IP complexes. Conclusions: The HDAC8 inhibitor ameliorates AHR and airway inflammation in animal model of allergic asthma through reducing HDAC8-Gal-3 interaction and M2 macrophage polarization.

Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma

“…HDAC8 has been shown to have increased enzymatic activity and play a pathogenic role in pulmonary asthma; when mice in a model of allergic asthma were exposed to ovalbumin (OVA), the level of HDAC8 protein expression was significantly increased in the lungs, together with high numbers of CD68 and CD163 macrophages. Treatment with the specific HDAC8 inhibitor PCI-34051 reduced these effects [32]. Another study found that PCI-34051 downregulated inflammatory cytokines in peripheral blood mononuclear cells (IL-18, IL-1b, MIP-1b, MCP-1, TNFa and IL-6) [33].…”

Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

“…Pharmacyclic’s PCI-34051 ( 52 , Figure ) was the first to exhibit high selectivity for HDAC8 and is the most widely used tool compound for this isoform . Newer examples include Huang’s cinnamoyl terphenylhydroxamic acid WK2-16 ( 53 ) and Beeler’s phenylalanine derived hydroxamic acid 54 . , In animal models, selective HDAC8 inhibitors have shown promise in neuroblastoma as well as different inflammatory settings such as hypertensive inflammation, neuroinflammation, and airway inflammation . Recently, 52 was shown to resensitize melanoma tumor xenograft cells to inhibition by the tyrosine kinase inhibitor erlotinib …”

Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms

“…Indeed, we performed independent experiments using cell-free assays indicating that LSF did not inhibit any of the other metal-dependent HDAC enzymes at biologically relevant concentrations (mM range for HDAC3, HDAC6, and HDAC7 and undetectable for others). This is an interesting observation as it has been previously shown that a potent specific HDAC8 inhibitor (PCI-34501), attenuated airway responses in OVA-sensitized mice 59 .…”