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

Meng-Lu Li,Yuan Ren,Jian Kang,Xin-Ming Su,Ling-Fei Kong,Xuan Zhao

doi:10.1186/s12931-020-1322-5

Meng-Lu Li, Yuan Ren + Show 4 more

Open Access

https://doi.org/10.1186/s12931-020-1322-5

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Abstract

BackgroundThis study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation.MethodsMice 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-β-methacholine 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).ResultsSignificant 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.ConclusionsThe HDAC8 inhibitor ameliorates AHR and airway inflammation in animal model of allergic asthma through reducing HDAC8-Gal-3 interaction and M2 macrophage polarization.

Highlights

This study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation
It has been reported that increased influx of macrophages in lungs has been recognized as the pathogenesis of allergic asthma [10], whereas the macrophages are polarized into two phenotypes of M1 and M2 in inflammatory responses to pathogens [11, 12]
Characterization of allergen-induced airway response AHR and airway allergic inflammation were measured in mice exposed to either normal saline (NS) or OVA in presence and absence of BUD or PCI-34051, respectively

Summary

Introduction

This study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation. It has been reported that increased influx of macrophages in lungs has been recognized as the pathogenesis of allergic asthma [10], whereas the macrophages are polarized into two phenotypes of M1 (classically activated macrophages) and M2 (alternatively activated macrophages) in inflammatory responses to pathogens [11, 12]. Gal-3 as a member of the beta-galactoside-binding protein family plays an important role in cell-cell adhesion, cell-matrix interactions and inflammation [14]. This protein involves the pathogenesis of asthma [15]

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