S1PR2 Inhibition Attenuates Allergic Asthma Possibly by Regulating Autophagy

Abstract

This study is to investigate the role of Sphingosine-1-phosphate (S1P) in the asthma progression, and the involvement of autophagy. Airway remodeling mice were subjected to the HE, PAS, and Masson staining. Protein expression levels in the tissues, samples and model cells were detected with ELISA, Western blot analysis, and immunohistochemical/immunofluorescent analysis. The S1P2 receptor antagonist JTE-013 decreased the inflammatory cell infiltration and goblet cell production in asthmatic mice tissues. The IL-1, IL-4, IL-5 and serum IgE contents were decreased in bronchoalveolar lavage fluid, while the Beclin1 expression in lung tissues was decreased. The LC3B1 to LC-3B2 conversion was decreased, with increased P62 accumulation and decreased p-P62 expression. In airway remodeling mice, JTE-013 significantly decreased collagen deposition in lung tissues and decreased smooth muscle cell smooth muscle activating protein expression. In lung tissue, the expression levels of Beclin1 were decreased, with decreased LC3B1 to LC-3B2 conversion, as well as the increased P62 accumulation and decreased p-P62 expression. However, these effects were reversed by the RAC1 inhibitor EHT 1864. Similar results were observed for the silencing of S1P2 receptor in the cells, as shown by the decreased Beclin1 expression, decreased LC3B1 to LC-3B2 conversion, increased P62 accumulation, and decreased p-P62 expression. The smooth muscle activators were significantly decreased in the JTE-013 and EHT1864 groups, and the EHT 1864 + S1P2-SiRNA expression level was increased. S1P is involved in the progression of asthma and airway remodeling, which may be related to the activation of S1PR2 receptor and inhibition of autophagy through RAC1.

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

“…These results unveiled a previously unappreciated ability of neutrophil CC1 to regulate autophagy via the S1PR2/S1PR3 axis. The mechanism by which autophagy may affect different cell types remains controversial ( 46 , 47 ). We utilized pharmacological inhibitors to investigate the impact of S1PR2/S1PR3 signaling on autophagy, with Baf A1–pretreated S1P-stimulated neutrophils exhibiting enhanced LC3B-2/p62 expression and aggravated NET formation.…”

Autophagy: A Friend or Foe in Allergic Asthma?

“…Remarkably, administration of JTE-013, a Sphingosine-1-phosphate receptor 2 (S1PR2) antagonist, in a mouse model of OVA-induced chronic airway inflammation and remodeling, decreased inflammatory cell recruitment and mucus production, reduced BAL IL-1, IL-4, IL-5, and serum IgE levels and attenuated collagen deposition and smooth muscle cell-activating proteins in the lungs. JTE-013 effects were accompanied by decreased Beclin-1 levels and LC3II/LC3I conversion and increased p62 accumulation, indicative of dampened autophagy [153].…”

Rac1, A Potential Target for Tumor Therapy

“…Studies have shown that Rac1 plays an important role in the contraction of various smooth muscles, such as bronchial smooth muscle, bladder smooth muscle, and prostate smooth muscle (180)(181)(182)(183). Although both EHT1864 and NSC23766 are Rac1 inhibitors, they have different pharmacological mechanisms in the inhibition of different smooth muscles (182,184,185), and EHT1864 tends to perform better (186,187). In recent years, new Rac1 inhibitors have been continuously developed.…”