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Open Access 01-12-2024 | Research

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

Authors: Linghui Meng, Dingqian Hao, Yuan Liu, Peng Yu, Jinfeng Luo, Chunhao Li, Tianjiao Jiang, JinZhuang Yu, Qian Zhang, Shengyang Liu, Li Shi

Published in: Journal of Translational Medicine | Issue 1/2024

Abstract

Objectives

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.

Methods

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.

Results

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^phox, 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^phox. In vivo, knocking down LRRC8A reduced eosinophil infiltration, downregulated the expression of NOX1, NOX4, p22^phox IL-4, IL-5, and IL-13, and decreased NF-κB pathway activation.

Conclusion

LRRC8A drives the upregulation of NOX1, NOX4, and p22^phox, 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.

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Title: LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis
Authors: Linghui Meng
Dingqian Hao
Yuan Liu
Peng Yu
Jinfeng Luo
Chunhao Li
Tianjiao Jiang
JinZhuang Yu
Qian Zhang
Shengyang Liu
Li Shi
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-024-05853-w

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