BRCA1/BRCA2-containing complex subunit 3 (BRCC3) serves as a deubiquitinating enzyme contributing to multiple inflammation-related disorders. However, the role of BRCC3 in modulating airway inflammation in asthma has not been investigated. This study aimed to examine the role of BRCC3 in airway inflammation using a mouse model of asthma induced by ovalbumin (OVA). BRCC3 levels were found to be elevated in mice with asthma. BRCC3 knockout (KO) mice demonstrated a notable improvement in pathological changes, accompanied by reduced levels of inflammatory cell infiltration and inflammatory cytokines, compared to wild-type (WT) mice following OVA challenge. The NLRP3 inflammasome was high activated in asthmatic mice, which was restrained by BRCC3 KO, as companied by a decrease in NLRP3, ASC, cleaved Caspase-1, cleaved Gasdermin D (GSDMD), IL-1β, and IL-18. In vitro studies demonstrated BRCC3 levels increased in airway epithelial cells in response to house dust mite (HDM) stimulation, depending on the dose and duration of exposure. Silencing BRCC3 in airway epithelial cells protected against HDM-induced cell injury and inflammation, along with inhibiting the NLRP3 inflammasome and pyroptosis. Conversely, the overexpression of BRCC3 in airway epithelial cells worsened DM-induced cell injury and inflammation while also enhancing the NLRP3 inflammasome and pyroptosis. Further investigations revealed that silencing BRCC3 increased the ubiquitination of NLRP3, whereas overexpressing BRCC3 decreased it. Pharmacological inhibition of the NLRP3 inflammasome diminished the effects of BRCC3 overexpression on the inflammation and pyroptosis induced by HDM in airway epithelial cells. Overall, these findings underscore the importance of BRCC3 in the pathogenesis of asthma. Deletion of BRCC3 alleviates airway inflammation in asthma by impeding the activation of the NLRP3 inflammasome, thus indicating that BRCC3 could serve as a potential target for asthma therapy.
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http://dx.doi.org/10.1016/j.intimp.2024.113720 | DOI Listing |
J Ethnopharmacol
December 2024
Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China. Electronic address:
Ethnopharmacological Relevance: Delayed tissue-type plasminogen activator (t-PA) thrombolysis, which has a restrictive therapeutic time window within 4.5 h following ischemic stroke (IS), increases the risk of hemorrhagic transformation (HT) and subsequent neurotoxicity. Studies have shown that the NLRP3 inflammasome activation reversely regulated by the PGC-1α leads to microglial polarization and pyroptosis to cause damage to nerve cells and the blood-brain barrier.
View Article and Find Full Text PDFCell Signal
December 2024
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China. Electronic address:
Through bioinformatics screening, we previously found that AlkB homolog 5 (ALKBH5) expression, an mA demethylase, was higher in patients with heart failure than in the normal population. This study aimed to investigate the molecular mechanisms by which ALKBH5 regulates heart failure. We established a myocardial infarction (MI)-induced heart failure model in rats in vivo and an in vitro hypoxia model using rat primary cardiac fibroblasts (RCFs).
View Article and Find Full Text PDFJ Hazard Mater
December 2024
College of Wildlife and Protected Area, Northeast Forestry University, Harbin, Heilongjiang 150040, PR China. Electronic address:
Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking.
View Article and Find Full Text PDFFASEB J
December 2024
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Intervertebral disc degeneration (IVDD), is one of the leading causes of low back pain. Inflammation is considered to be the main pathophysiological process of IVDD. The nucleotide-binding domain and leucine-rich pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory responses are critically involved in the progression of IVDD.
View Article and Find Full Text PDFCell Commun Signal
December 2024
Department of Immunology, School of Basic Medical Sciences, Cheeloo college of Medicine, Shandong University, Jinan, 250012, China.
Background: The NOD-like receptor protein (NLRP)3 inflammasome is at the signaling hub center to instigate inflammation in response to pathogen infection or oxidative stress, and its tight control is pivotal for immune defense against infection while avoiding parallel intensive inflammatory tissue injury. Acetylation of NLRP3 is critical for the full activation of NLRP3 inflammasome, while the precise regulation of the acetylation and deacetylation circuit of NLRP3 protein remained to be fully understood.
Methods: The interaction between histone deacetylase 10 (HDAC10) and NLRP3 was detected by immunoprecipitation and western blot in the HDAC10 and NLRP3 overexpressing cells.
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