Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea

Yasuda, Shingo; Sumioka, Takayoshi; Iwanishi, Hiroki; Okada, Yoshinori; Miyajima, Masayasu; Ichikawa, Kana; Reinach, Peter S.; Saika, Shizuya

doi:10.1038/s41374-020-00505-1

Cited by 10 publications

(3 citation statements)

References 41 publications

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“…Abnormal proliferation and migration of ASMCs play an important role in airway hyperresponsiveness and airway remodeling in asthma [ 108 , 116 , 117 ]. S1P is a natural, multifunctional, bioactive phospholipid molecule that is involved in cell proliferation, differentiation, migration, contraction, and vasculogenesis [ 82 , 108 , 118 – 120 ]. It is reported that the level of S1P in bronchoalveolar lavage fluid is significantly increased in asthmatic patients, and the S1P stimulates the proliferation, migration, and contraction of ASMC in vitro [ 108 ].…”

Section: The Hippo Signaling Pathway and Respiratory Diseasesmentioning

confidence: 99%

Hippo signaling pathway and respiratory diseases

Tang

Yangzhong

et al. 2022

Cell Death Discov.

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The hippo signaling pathway is a highly conserved evolutionary signaling pathway that plays an important role in regulating cell proliferation, organ size, tissue development, and regeneration. Increasing evidences consider that the hippo signaling pathway is involved in the process of respiratory diseases. Hippo signaling pathway is mainly composed of mammalian STE20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), WW domain of the Sav family containing protein 1 (SAV1), MOB kinase activator 1 (MOB1), Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ), and members of the TEA domain (TEAD) family. YAP is the cascade effector of the hippo signaling pathway. The activation of YAP promotes pulmonary arterial vascular smooth muscle cells (PAVSMCs) proliferation, which leads to pulmonary vascular remodeling; thereby the pulmonary arterial hypertension (PAH) is aggravated. While the loss of YAP leads to high expression of inflammatory genes and the accumulation of inflammatory cells, the pneumonia is consequently exacerbated. In addition, overexpressed YAP promotes the proliferation of lung fibroblasts and collagen deposition; thereby the idiopathic pulmonary fibrosis (IPF) is promoted. Moreover, YAP knockout reduces collagen deposition and the senescence of adult alveolar epithelial cells (AECs); hence the IPF is slowed. In addition, hippo signaling pathway may be involved in the repair of acute lung injury (ALI) by promoting the proliferation and differentiation of lung epithelial progenitor cells and intervening in the repair of pulmonary capillary endothelium. Moreover, the hippo signaling pathway is involved in asthma. In conclusion, the hippo signaling pathway is involved in respiratory diseases. More researches are needed to focus on the molecular mechanisms by which the hippo signaling pathway participates in respiratory diseases.

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Section: The Hippo Signaling Pathway and Respiratory Diseasesmentioning

confidence: 99%

Hippo signaling pathway and respiratory diseases

Tang

Yangzhong

et al. 2022

Cell Death Discov.

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“…In addition, we used rhodamine phalloidin to stain the cytoskeleton, and found that the inhibition of S1PR3 significantly reduced the LPS-induced disruption of the cytoskeleton. Moreover, Yasuda et al [ 41 ] reported that the S1PR3 mediated the VE-cadherin mRNA levels in two types of endothelial cells. In a murine ventilator-induced lung injury model, S1PR3 induced endothelial barrier loss through ADAM10-mediated VE-cadherin cleavage [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

S1PR3 inhibition protects against LPS-induced ARDS by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation

Peng,

Tang,

et al. 2024

J Transl Med

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Background Inflammation and endothelial barrier dysfunction are the major pathophysiological changes in acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor, has been found to mediate inflammation and endothelial cell (EC) integrity. However, the function of S1PR3 in ARDS has not been fully elucidated. Methods We used a murine lipopolysaccharide (LPS)-induced ARDS model and an LPS- stimulated ECs model to investigate the role of S1PR3 in anti-inflammatory effects and endothelial barrier protection during ARDS. Results We found that S1PR3 expression was increased in the lung tissues of mice with LPS-induced ARDS. TY-52156, a selective S1PR3 inhibitor, effectively attenuated LPS-induced inflammation by suppressing the expression of proinflammatory cytokines and restored the endothelial barrier by repairing adherens junctions and reducing vascular leakage. S1PR3 inhibition was achieved by an adeno-associated virus in vivo and a small interfering RNA in vitro. Both the in vivo and in vitro studies demonstrated that pharmacological or genetic inhibition of S1PR3 protected against ARDS by inhibiting the NF-κB pathway and improving mitochondrial oxidative phosphorylation. Conclusions S1PR3 inhibition protects against LPS-induced ARDS via suppression of pulmonary inflammation and promotion of the endothelial barrier by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation, indicating that S1PR3 is a potential therapeutic target for ARDS.

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“…Although investigations on S1P in the cornea have been under documented in the past, two recent studies have demonstrated the effects of SphK1/S1P in mouse corneas. Yasuda et al, 2021, revealed that TGF-β1-induced injury increased S1P via SphK1 upregulation modulated by S1PR3 and VEGF-A and angiogenesis [104]. Wilkerson et al, 2022, reported that SphK1 knockout mice had reduced corneal neovascularization following injury [55].…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Nicholas,

Basu,

Mandal

et al. 2024

IJMS

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Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I2; prevention groups; (4) S1P/β1; and (5) I2/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.

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Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea

Cited by 10 publications

References 41 publications

Hippo signaling pathway and respiratory diseases

Hippo signaling pathway and respiratory diseases

S1PR3 inhibition protects against LPS-induced ARDS by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

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