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

Objectives: Allergic rhinitis (AR) is a multifactorial disorder with diverse underlying mechanisms. Emerging evidence indicates that LRRC8A plays a crucial role in cellular stability, immune cell activation, and inflammatory processes. However, the contribution of LRRC8A to AR-associated inflammation and its underlying mechanisms remain poorly understood.

Methods: The expression of LRRC8A was assessed in AR patients using qRT-PCR and Western blotting, and its association with clinical characteristics of AR was analyzed. In vitro, a Th2 inflammation model was established by stimulating HNEpCs with IL-13, followed by either LRRC8A knockout or overexpression. To explore the mechanisms underlying AR development during LRRC8A overexpression, the NOX1/NOX4 inhibitor (GKT137831) and chloride channel inhibitor (DCPIB) were employed. An OVA-induced AR model with nasal mucosa LRRC8A knockdown further confirmed the regulatory role of LRRC8A in AR inflammation.

Results: In AR patients, both mRNA and protein levels of LRRC8A were significantly elevated, showing a positive correlation with NADPH oxidase subunits and Th2 inflammatory markers. In vitro, IL-13 stimulation led to the upregulation of LRRC8A in HNEpCs, along with increased expression of NOX1, NOX4, and p22phox, mitochondrial dysfunction, and activation of the NF-κB pathway. LRRC8A knockout reversed these effects. In nasal mucosal epithelial cells, both DCPIB and GKT137831 completely blocked the mitochondrial dysfunction induced by LRRC8A overexpression, preventing the upregulation of NOX1, NOX4, and p22phox. In vivo, LRRC8A knockdown reduced eosinophil infiltration, decreased the expression of NOX1, NOX4, p22phox, IL-4, IL-5, and IL-13, and suppressed NF-κB pathway activation.

Conclusion: LRRC8A promotes the upregulation of NOX1, NOX4, and p22phox, resulting in ROS overproduction, mitochondrial dysfunction, and NF-κB pathway activation, which together drive nasal mucosal inflammation in AR. LRRC8A may represent a promising therapeutic target for the treatment of AR.