Deletion of BRCC3 ameliorates airway inflammation in asthma by inhibiting the activation of NLRP3 inflammasome.

Abstract

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.