Int J Biol Sci 2023; 19(5):1597-1615. doi:10.7150/ijbs.80256 This issue Cite

Research Paper

Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation

Shanshan Wang1, Zhen Tian1, Yanjiao Lu1, Zhenli Huang1, Yan Fan1, Boyu Li1, Hongyan Zheng1, Xiaojie Wu2, Meijia Wang1✉, Jianping Zhao1✉, Jungang Xie1✉

1. Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
2. Department of Respiratory and Critical Care Medicine, Wuhan NO.1 Hospital, Wuhan Hospital of traditional Chinese and Western Medicine, Wuhan 430022, China

Citation:
Wang S, Tian Z, Lu Y, Huang Z, Fan Y, Li B, Zheng H, Wu X, Wang M, Zhao J, Xie J. Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation. Int J Biol Sci 2023; 19(5):1597-1615. doi:10.7150/ijbs.80256. https://www.ijbs.com/v19p1597.htm
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Abstract

Graphic abstract

Patients with eosinophilic asthma react well to conventional treatment of asthma while individualized therapy for non-eosinophilic endotypes have yet to be developed. Dysregulated sphingosine metabolites are associated with the pathophysiology of different asthma endotypes with their receptors involved. However, whether the sphingosine-1-phosphate receptor 4 (S1PR4) contributes to disease progression of asthma remains underappreciated. In this study, we demonstrated that sphingosine metabolism was disturbed in asthma while it could not be used to distinguish between different endotypes of asthma. S1PR4, a vital receptor of bioactive sphingosine metabolites and mainly expressed in macrophages, exhibited lower expression both in patients and experimental mice with neutrophilic airway inflammation. Additionally, S1pr4 deficiency aggravated the OVA/LPS-induced pulmonary inflammation in mice along with a significant up-regulation in M1 macrophage activation. Mechanistic studies showed that S1PR4 was strongly connected to bioactive oxylipins concurrent with bounding to formyl peptide receptor 2 to influence the phosphorylation of JNK and contributed to the macrophage M1 program, which in turn secreted amounts of inflammatory cytokines associated to the inflammatory response of neutrophilic asthma. Furthermore, treating mice with S1PR4 agonist CYM50308 was characterized by less pulmonary inflammatory infiltration. Our research indicates S1PR4 a promising therapeutic target for non-eosinophilic phenotypes of asthma.

Keywords: sphingosine metabolism, S1PR4, macrophage, FPR2, neutrophilic asthma


Citation styles

APA
Wang, S., Tian, Z., Lu, Y., Huang, Z., Fan, Y., Li, B., Zheng, H., Wu, X., Wang, M., Zhao, J., Xie, J. (2023). Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation. International Journal of Biological Sciences, 19(5), 1597-1615. https://doi.org/10.7150/ijbs.80256.

ACS
Wang, S.; Tian, Z.; Lu, Y.; Huang, Z.; Fan, Y.; Li, B.; Zheng, H.; Wu, X.; Wang, M.; Zhao, J.; Xie, J. Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation. Int. J. Biol. Sci. 2023, 19 (5), 1597-1615. DOI: 10.7150/ijbs.80256.

NLM
Wang S, Tian Z, Lu Y, Huang Z, Fan Y, Li B, Zheng H, Wu X, Wang M, Zhao J, Xie J. Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation. Int J Biol Sci 2023; 19(5):1597-1615. doi:10.7150/ijbs.80256. https://www.ijbs.com/v19p1597.htm

CSE
Wang S, Tian Z, Lu Y, Huang Z, Fan Y, Li B, Zheng H, Wu X, Wang M, Zhao J, Xie J. 2023. Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation. Int J Biol Sci. 19(5):1597-1615.

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