HDAC4 depletion ameliorates IL‐13‐triggered inflammatory response and mucus production in nasal epithelial cells via activation of SIRT1/NF‐κB signaling

Abstract

Introduction Allergic rhinitis (AR) is frequently known as a chronic respiratory disease with a global high prevalence. The pivotal roles of histone deacetylase 4 (HDAC4) in multiple human diseases have been underlined by numerous studies. Nevertheless, whether HDAC4 is implicated in AR remains to be elaborated. The objective of the current study is to clarify the impacts of HDAC4 on AR. Methods First, human nasal epithelial cells (hNECs) were pretreated by interleukin‐13 (IL‐13). HDAC4 expression in hNECs with the presence or absence of IL‐13 treatment was tested by quantitative reverse‐transcription polymerase chain reaction (RT‐qPCR) and western blot. Following, after HDAC4 was depleted, levels of histamine, Immunoglobulin E (IgE) and inflammatory factors were analyzed by ELISA assay. Then, Mucin‐5AC (MUC5AC) expression was examined through RT‐qPCR, western blot, and IF assay. Western blot was to analyze the expression of sirtuin 1 (SIRT1)/nuclear factor‐kappaB (NF‐κB) signaling‐related proteins. After IL‐13‐induced hNECs were cotransfected with HDAC4 interference plasmids and SIRT1 inhibitor EX527, the functional experiments above were conducted again. Results The experimental data in this study presented that HDAC4 expression was increased in IL‐13‐induced hNECs. Silencing of HDAC4 cut down the levels of histamine, IgE and inflammatory factors and the expression of MUC5AC. Additionally, knockdown of HDAC4 led to the activation of SIRT1/NF‐κB signaling. Further, the downregulated levels of histamine, IgE and inflammatory factors and the expression of MUC5AC imposed by HDAC4 interference were all reversed by EX527. Conclusions In short, HDAC4 inhibition activated SIRT1/NF‐κB signaling to mitigate inflammatory response and mucus production in IL‐13‐treated nasal epithelial cells in AR.

CircARF3 Mitigates Allergic Rhinitis through Targeting microRNA-205-5p/Sirtuin 5 Axis

“…Here, we discovered SIRT5 overexpression mitigated cell apoptosis in IL-4/IL-13-treated NEpCs, suggesting the potential anti-apoptotic activity of SIRT5 in AR, which was also in line with that of glucolipotoxicitytreated pancreatic β cells and cisplatin-treated kidney cells [46,47]. SIRT5 function in AR was likewise consistent with SIRT1, another member of SIRT family [48]. Furthermore, we investigated the relationship between miR-205-5p and SIRT5 and discovered that miR-205-5p targeted SIRT5 in AR.…”

ZIP4 upregulation aggravates nucleus pulposus cell degradation by promoting inflammation and oxidative stress by mediating the HDAC4-FoxO3a axis

“…In nasal epithelial cells, the HDAC4 profile was elevated upon IL-13 treatment, which repressed SIRT1 and initiated NF-κB signaling. HDAC4 knockdown activated SIRT1/NF-κB signaling and mitigated inflammatory responses and mucus generation in nasal epithelial cells after IL-13 treatment [39]. NF-κB, an indispensable transcription factor, plays a pivotal role in the modulation of IL-1β-elicited cell viability, migration, apoptosis, and inflammatory response in both human chondrocytes and NP cells [40][41][42].…”

The role of deacetylase SIRT1 in allergic diseases

“…IL-13 secreted by Th2 cells is considered to be a central mediator of allergic inflammation, stimulating mucin synthesis and secretion ( 80 ). Studies have shown that IL-13 can induce inflammatory responses and mucus secretion in human nasal epithelial cells (hNEC), and the severity of AR can be determined based on the expression of IL-13 ( 81 ). Nrf2 and Kelch-like ECH associated protein (Keap 1) combine as dimers in the cytoplasm.…”

“…Consistent with this, SIRT1 mediates acetylation modification of NF-κB p65, inactivating the NF-κB pathway ( 86 ). Interfering with HDAC4 can restore the expression of SIRT1 and reduce the inflammatory response caused by IL-13 by activating the SIRT1/NF-κB pathway ( 81 ).…”