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Antioxidants
Volume 11
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10.3390/antiox11102050
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Article

Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages

by
Tao Yang
1,†,
Qingguo Zhao
2,†,
Meijun Hu
1,
Simin Pan
2,3,
Linying Zhang
2,3,
Ruoxi Zhu
1,
Bowen Zhou
1,
Xuanhe Feng
1,
Zhenhua Gao
1,
Zhao Zhu
1,
Yu Zhang
3,
Liang Hu
1,4,*,
Fei Liu
2,* and
Zhaochen Shan
1,*
1
Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, China
2
Department of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA
3
Department of Statistics, Texas A&M University, College Station, TX 77843, USA
4
Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, Capital Medical University School of Stomatology, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Antioxidants 2022, 11(10), 2050; https://doi.org/10.3390/antiox11102050
Submission received: 31 July 2022 / Revised: 8 October 2022 / Accepted: 13 October 2022 / Published: 18 October 2022
(This article belongs to the Special Issue Oxidative Stress and Gene Regulation)
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Abstract

Radiotherapy for head-and-neck cancers frequently causes long-term hypofunction of salivary glands that severely compromises quality of life and is difficult to treat. Here, we studied effects and mechanisms of Sphingosine-1-phosphate (S1P), a versatile signaling sphingolipid, in preventing irreversible dry mouth caused by radiotherapy. Mouse submandibular glands (SMGs) were irradiated with or without intra-SMG S1P pretreatment. The saliva flow rate was measured following pilocarpine stimulation. The expression of genes related to S1P signaling and radiation damage was examined by flow cytometry, immunohistochemistry, quantitative RT-PCR, Western blotting, and/or single-cell RNA-sequencing. S1P pretreatment ameliorated irradiation-induced salivary dysfunction in mice through a decrease in irradiation-induced oxidative stress and consequent apoptosis and cellular senescence, which is related to the enhancement of Nrf2-regulated anti-oxidative response. In mouse SMGs, endothelial cells and resident macrophages are the major cells capable of producing S1P and expressing the pro-regenerative S1P receptor S1pr1. Both mouse SMGs and human endothelial cells are protected from irradiation damage by S1P pretreatment, likely through the S1pr1/Akt/eNOS axis. Moreover, intra-SMG-injected S1P did not affect the growth and radiosensitivity of head-and-neck cancer in a mouse model. These data indicate that S1P signaling pathway is a promising target for alleviating irradiation-induced salivary gland hypofunction.
Keywords: sphingosine-1-phosphate signaling; salivary glands; irradiation; head and neck cancers; endothelial cells; resident macrophages sphingosine-1-phosphate signaling; salivary glands; irradiation; head and neck cancers; endothelial cells; resident macrophages
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MDPI and ACS Style

Yang, T.; Zhao, Q.; Hu, M.; Pan, S.; Zhang, L.; Zhu, R.; Zhou, B.; Feng, X.; Gao, Z.; Zhu, Z.; et al. Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages. Antioxidants 2022, 11, 2050. https://doi.org/10.3390/antiox11102050

AMA Style

Yang T, Zhao Q, Hu M, Pan S, Zhang L, Zhu R, Zhou B, Feng X, Gao Z, Zhu Z, et al. Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages. Antioxidants. 2022; 11(10):2050. https://doi.org/10.3390/antiox11102050

Chicago/Turabian Style

Yang, Tao, Qingguo Zhao, Meijun Hu, Simin Pan, Linying Zhang, Ruoxi Zhu, Bowen Zhou, Xuanhe Feng, Zhenhua Gao, Zhao Zhu, and et al. 2022. "Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages" Antioxidants 11, no. 10: 2050. https://doi.org/10.3390/antiox11102050

APA Style

Yang, T., Zhao, Q., Hu, M., Pan, S., Zhang, L., Zhu, R., Zhou, B., Feng, X., Gao, Z., Zhu, Z., Zhang, Y., Hu, L., Liu, F., & Shan, Z. (2022). Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages. Antioxidants, 11(10), 2050. https://doi.org/10.3390/antiox11102050

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