Unleashing AdipoRon’s Potential: A Fresh Approach to Tackle Pseudomonas aeruginosa Infections in Bronchiectasis via Sphingosine Metabolism Modulation

Abstract

Jia-wei Xu,1,2,* Fang-fang Chen,1,* Ying-hui Qv,1,* Cong-cong Sun,1 Dong Zhang,1,2 Zhi Guo,1 Yu-jiao Wang,3 Jun-fei Wang,4 Tian Liu,4 Liang Dong,1,2 Qian Qi1,2 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Characteristic Laboratory of Clinical Transformation of Respiratory Biological Immunity and Regenerative Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, 250014, People’s Republic of China; 3Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Laboratory Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian Qi, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, #16766, Jingshi Road, Jinan City, Shandong Province, 250014, People’s Republic of China, Tel [phone], Email [email protected]: Bronchiectasis patients are prone to Pseudomonas aeruginosa infection due to decreased level of sphingosine in airway. Adiponectin receptor agonist AdipoRon activates the intrinsic ceramidase activity of adiponectin receptor 1 (AdipoR1) and positively regulates sphingosine metabolism. This study aimed to investigate the potential therapeutic benefit of AdipoRon against Pseudomonas aeruginosa infection.Methods: A mouse model of Pseudomonas aeruginosa lung infection and a co-culture model of human bronchial epithelial cells with Pseudomonas aeruginosa were established to explore the protective effect of AdipoRon. Liquid chromatography-mass spectrometry was used to detect the effect of AdipoRon on sphingosine level in lung of Pseudomonas aeruginosa-infected mouse models.Results: The down-regulation of adiponectin and AdipoR1 in airway of bronchiectasis patients was linked to Pseudomonas aeruginosa infection. By activating AdipoR1, AdipoRon reduced Pseudomonas aeruginosa adherence on bronchial epithelial cells and protected cilia from damage in vitro. With the treatment of AdipoRon, the load of Pseudomonas aeruginosa in lung significantly decreased, and peribronchial inflammatory cell infiltration was lessened in vivo. The reduced level of sphingosine in the airway of Pseudomonas aeruginosa infected mice was replenished by AdipoRon, thus playing a protective role in the airway. Moreover, AdipoRon activated P-AMPKα/PGC1α, inhibited TLR4/P-NF-κB p65, and reduced expression of pro-apoptotic bax. However, the protective effect of AdipoRon on resisting Pseudomonas aeruginosa infection was weakened when AdipoR1 was knocked down.Conclusion: AdipoRon protects bronchial epithelial cells and lung by enhancing their resistance to Pseudomonas aeruginosa infection. The mechanism might be modulating sphingosine metabolism and activating P-AMPKα/PGC1α while inhibiting TLR4/P-NF-κB p65.Keywords: AdipoRon, Pseudomonas aeruginosa, bronchiectasis, AdipoR1, sphingosine metabolism

Keywords

• adiporon
• pseudomonas aeruginosa
• bronchiectasis
• adipor1
• sphingosine metabolism