LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis

• Published in: Journal of translational medicine 2024-11, Vol.22 (1), p.1034-18, Article 1034
• Main Authors: Meng, Linghui, Hao, Dingqian, Liu, Yuan, Yu, Peng, Luo, Jinfeng, Li, Chunhao, Jiang, Tianjiao, Yu, JinZhuang, Zhang, Qian, Liu, Shengyang, Shi, Li
• Format: Article
• Language: English
• Subjects: Adult; Allergic rhinitis; Analysis; Animals; Care and treatment; Diagnosis; Female; Gene expression; Genetic aspects; Hay-fever; Humans; Inflammation - pathology; Interleukin-13 - metabolism; LRRC8A; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred BALB C; Mitochondria - metabolism; Mitochondrial diseases; NADPH oxidase; NADPH Oxidases - metabolism; Nasal Mucosa - metabolism; Nasal Mucosa - pathology; NF-kappa B - metabolism; Polymerase chain reaction; Reactive Oxygen Species - metabolism; Rhinitis, Allergic - metabolism; Rhinitis, Allergic - pathology; Signal Transduction; Testing; Th2 Cells - immunology; Th2 Cells - metabolism; Volume-regulated anion channel (VRAC)
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05853-w

Allergic rhinitis (AR) is a complex disorder with variable pathogenesis. Increasing evidence suggests that the LRRC8A is involved in maintaining cellular stability, regulating immune cell activation and function, and playing significant roles in inflammation. However, the involvement of LRRC8A in AR inflammation and its underlying mechanisms remain unclear. LRRC8A expression in AR patients, confirmed by qRT-PCR and Western blotting, was analyzed to investigate its relationship with the clinical characteristics of AR patients. In vitro, IL-13 stimulated HNEpCs to establish a Th2 inflammation model, with subsequent LRRC8A knockout or overexpression. NOX1/NOX4 inhibitor (GKT137831) and chloride channel inhibitor (DCPIB) were utilized to investigate AR development mechanisms during LRRC8A overexpression. An OVA-induced AR model with nasal mucosa LRRC8A knockdown confirmed LRRC8A's regulatory role in AR inflammation. LRRC8A mRNA and protein levels were significantly elevated in AR patients, positively correlating with NADPH oxidase subunits and Th2 inflammatory markers. In vitro, IL-13 stimulation of HNEpCs resulted in upregulation of LRRC8A and increased expression of NOX1, NOX4, and p22 , along with mitochondrial dysfunction and NF-κB pathway activation. The knockout of LRRC8A reversed these effects. In nasal mucosal epithelial cells, DCPIB and GKT137831 completely blocked mitochondrial dysfunction caused by the overexpression of LRRC8A, which led to up-regulation of NOX1, NOX4, and p22 . In vivo, knocking down LRRC8A reduced eosinophil infiltration, downregulated the expression of NOX1, NOX4, p22 IL-4, IL-5, and IL-13, and decreased NF-κB pathway activation. LRRC8A drives the upregulation of NOX1, NOX4, and p22 , leading to ROS overproduction and mitochondrial dysfunction. It also activates NF-κB, ultimately leading to nasal mucosal epithelial inflammation. LRRC8A may be a potential target for the treatment of AR.