Contribution of Pseudomonas aeruginosa - mediated club cell necroptosis to the bias of type 17 inflammation and steroid insensitivity in asthma.

Opportunistic pathogen infection is one of the important inducements for asthma exacerbation. Pseudomonas aeruginosa (PA) is a kind of dominant pathogenic bacteria in the respiratory tract that is associated with severe asthma, but the underlying mechanisms still remains unclear. To examine the role of PA infection in the bias of the inflammatory endotype in asthma and its effect on the sensitivity to steroid therapy. An adjusted HDM (House Dust Mite) -induced asthma model with PA inoculation in the airway was utilized to mimic the process of opportunistic PA infection in asthma, focusing on the interaction between bacteria and epithelium. Dexamethasone administration in vivo was used to test the sensitivity to steroid therapy. It was uncovered that PA could promote the loss of club cells in the necroptosis pattern through cellular CYP450 activation, leading to an imbalance of inflammatory response and steroid insensitivity. Club cell loss results in the activation of cellular E-cadherin/β-catenin axis in the rest of club cells for goblet metaplasia and mucus hypersecretion, as well as epithelial damage and GR downregulation for steroid resistance. For clinical applications, the necroptosis inhibitor Nec-1 can effectively relieve the pathological symptoms of asthma in vivo. Meanwhile, CCSP administration in the airway can regulate the pulmonary inflammation and restore the steroid sensitivity in asthma. These experiments provide a novel mechanism of concurrent PA infection in asthma through club cell necroptosis and the pathological consequences. Nec-1 treatment and CCSP supplementation may be possible therapeutic strategies for asthma treatment.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.