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

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.

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

“…Similarly, Megumi et al found that licochalcone A (39) inhibited IKK complex activation and IκB degradation via the covalently binding to amino acid residue Cys179 of IKKβ [159]. Additionally, some of dihyflavones, such as erioddictyol (40), naringenin (41), and pinocembrin ( 42), could interact with amino acid residues Thr23, Glu97, Cys99, and Asp166 in the ATP binding domain through hydrogen bonds to suppress the IKKβ activity [160].…”

“…IKKβ-mediated NF-κB pathway is a key signal transduction pathway involved in inflammatory response, angiogenesis, invasiveness, metastasis, and immune escape [39][40][41][42][43][44][45][46]. After this signaling pathway is activated by inflammatory factors, it promotes the expression of inflammatory factors at the transcriptional level as well, thus forming a loop and producing an amplification effect to aggravate inflammation response [47][48][49][50][51].…”

Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm?

“…However, there is limited and controversial information about the mechanisms controlled by S1PR4. S1PR4 may participate in the release of proinflammatory cytokines in activated macrophages and mediate the activation and maturation of dendritic cells [ 156 ], but also its absence exacerbates M1 polarization and pulmonary inflammation [ 157 ].…”