HDAC2 attenuates airway inflammation by suppressing IL-17A production in HDM-challenged mice

Abstract

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/− mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/− mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.

CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma

“…5, 6). It is known that IL-17A modulating the protective effects of HDAC2 on airway in ammation in asthma and HDAC2 activation and/or IL-17A downregulation could prevent allergic airway in ammation [13]. Moreover, RORγt transcriptionally upregulates IL-17A, indicating that CpG-ODN may suppress RORγt-associated IL-17A expression via HDAC2 in vitro in line with the above evidences.…”

“…3). Several reports have revealed decreased HDAC2 activity in smokers and sputum cells in patients with respiratory diseases, as well as in CS-exposed asthma mice [13,15,22,29]. Decreased HDAC2 amounts and activity are involved in steroid insensitivity and exacerbated disease in asthmatic individuals, indicating that insu cient transcriptional co-repressor amounts and activity might be critical for asthma pathogenesis [40].…”

“…Of interest, in the present study, the opposite tendency between HDAC2 and IL-17A was found, with HDAC2 downregulated while IL-17A was upregulated in CS-exposure asthmatic mice. Several studies have pointed out that the striking interaction between HDAC2 and IL-17A forms a vicious circle, leading to the exacerbation of asthma [13]. According to a study reported by Tianwei Lai et al [13], HDAC2 impairment upregulates IL-17A, whose de ciency restores HDAC2 reduction, highlighting HDAC2 as a mediator that affects the secretion of IL-17A, thereby causing Th17-polarized response.…”

“…Several studies have pointed out that the striking interaction between HDAC2 and IL-17A forms a vicious circle, leading to the exacerbation of asthma [13]. According to a study reported by Tianwei Lai et al [13], HDAC2 impairment upregulates IL-17A, whose de ciency restores HDAC2 reduction, highlighting HDAC2 as a mediator that affects the secretion of IL-17A, thereby causing Th17-polarized response. As demonstrated in our previous research, CpG-ODN alleviate airway in ammation and remodeling by affecting DC-mediated Th17 differentiation in CS-exposure asthma.…”

“…To be speci c, GCs decrease in ammatory reactions via HDAC2 recruitment to the promoters of proin ammatory genes, regulating their transcription [12]. According to several studies, HDAC2 activity is decreased in alveolar macrophages, peripheral blood mononuclear cells, and bronchial biopsies in asthma cases [13]. Moreover, studies have also demonstrated that HDAC2 protects airway in ammation in mouse and human epithelial cells.…”