Gasdermin B is an RNA sensor that promotes interferon response and airway inflammation

Rationale: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, often due to over-activated interferon response. How viral infection-induced interferon response subsequently leads to exuberant airway inflammation in genetically susceptible asthmatics remains largely unknown.

Methods: In primary human bronchial epithelial cells or human bronchial epithelial cell line, we generated GSDMB-overexpressing and -deficient cells. By performing qpcr, Elisa and co-immunoprecipitation (co-IP), we assessed the target of GSDMB to interferon response. In two independent cohorts, we analyzed the correlation between GSDMB and interferon response. Also, we generated a mice model with inducible expression of human unique GSDMB gene in mouse airway epithelial cells and established a repetitive RSV infection model in the neonatal stage to detect the role of GSDMB on RSV-induced inflammation.

Results: We demonstrate that gasdermin B encoded by GSDMB, one of the most significant asthma-susceptible genes at 17q21, acts as a novel RNA sensor, promoting MAVS-TBK1 signaling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and interferon-stimulated genes significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible and conditional expression of human GSDMB gene in mouse airway epithelium leads to the enhanced interferon response, increased airway inflammation with mucus hyper-secretion upon neonatal respiratory syncytial virus infection.

Conclusion: GSDMB, a novel RNA sensor, promotes interferon response and enhances airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.