circRNA Mediates Silica-Induced Macrophage Activation Via HECTD1/ZC3H12A-Dependent Ubiquitination

Abstract

Rationale: Phagocytosis of silicon dioxide (SiO2) into lung cells causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Circular RNAs (circRNAs) are a subclass of non-coding RNAs detected within mammalian cells; however, researchers have not determined whether circRNAs are involved in the pathophysiological process of silicosis. The upstream molecular mechanisms and functional effects on cell apoptosis, proliferation and migration were investigated to elucidate the role of circRNAs in SiO2-induced inflammation in pulmonary macrophages.Methods: Primary cultures of alveolar macrophages from healthy donors and patients as well as the RAW264.7 macrophage cell line were used to explore the functions of circHECTD1 (HECT domain E3 ubiquitin protein ligase 1) in macrophage activation.Results: The results of the experiments indicated that 1) SiO2 concomitantly decreased circHECTD1 levels and increased HECTD1 protein expression; 2) circHECTD1 and HECTD1 were involved in SiO2-induced macrophage activation via ubiquitination; and 3) SiO2-activated macrophages promoted fibroblast proliferation and migration via the circHECTD1/HECTD1 pathway. Tissue samples from silicosis patients confirmed the upregulation of HECTD1.Conclusions: Our study elucidated a link between SiO2-induced macrophage activation and the circHECTD1/HECTD1 pathway, thereby providing new insight into the potential use of HECTD1 in the development of novel therapeutic strategies for treating silicosis.

Silica‐induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation

“…Previous data from our laboratory suggested that macrophage activation and apoptotic marker expression were increased in macrophages from the BALF of patients with silicosis (27, 32). We, therefore, extended our cell culture experiments to include examination of a human macrophage cell line and cells from patients with silicosis to validate our findings.…”

The role of circular RNA HECTD1 expression in disease risk, disease severity, inflammation, and recurrence of acute ischemic stroke

“…6 Recent studies have exhibited the role of circRNA HECTD1 in the development and progression of several diseases such as AIS and silicosis. 7,8 For example, a study discloses that knockdown of circRNA HECTD1 attenuates infract size and decreases neurological deficits in cerebral ischemia transient middle cerebral artery occlusion mouse (tMCAO) stroke models. 7 Besides that, a preliminary study based on primary cultures of alveolar macrophages from silicosis patients demonstrates that circRNA HECTD1 involves in SiO 2 -mediated inflammation cascade.…”

“…7 Besides that, a preliminary study based on primary cultures of alveolar macrophages from silicosis patients demonstrates that circRNA HECTD1 involves in SiO 2 -mediated inflammation cascade. 8 Based on the role of circRNA HECTD1 in enlarging stroke infarct size, accelerating neurological deficits, and inflammation from previous studies, we hypothesized that circRNA HECTD1 may be involved in the development and progression of AIS. However, no clinical studies have been done in evaluating the role of circRNA HECTD1 in AIS until now.…”

Regulatory network of two circRNAs and an miRNA with their targeted genes under astilbin treatment in pulmonary fibrosis

“…Bachmayr‐Heyda et al discovered a negative correlation of circRNA abundance and proliferation in lung fibrosis . Chao et al found that circHECTD1 promotes silica‐induced pulmonary fibrosis via HECTD1 . A recent study from our laboratory based on a circRNA microarray analysis identified 67 significantly dysregulated circRNAs in IPF patients, indicating the fundamental roles of circRNAs in pathological processes of lung fibrosis .…”

“…31 Chao et al found that circHECTD1 promotes silica-induced pulmonary fibrosis via HECTD1. 32,33 A recent study from our laboratory based on a circRNA microarray analysis identified 67 significantly dysregulated circRNAs in IPF patients, indicating the fundamental roles of circRNAs in pathological processes of lung fibrosis. 19 In this study, 145 differentially expressed circRNAs were identified under astilbin treatment using RNA sequencing.…”