Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages
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 irrevers...
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MDPI AG
2022-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/10/2050 |
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| author | Tao Yang Qingguo Zhao Meijun Hu Simin Pan Linying Zhang Ruoxi Zhu Bowen Zhou Xuanhe Feng Zhenhua Gao Zhao Zhu Yu Zhang Liang Hu Fei Liu Zhaochen Shan |
| author_facet | Tao Yang Qingguo Zhao Meijun Hu Simin Pan Linying Zhang Ruoxi Zhu Bowen Zhou Xuanhe Feng Zhenhua Gao Zhao Zhu Yu Zhang Liang Hu Fei Liu Zhaochen Shan |
| author_sort | Tao Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:49:03Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-09T20:49:03Z |
| publishDate | 2022-10-01 |
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| series | Antioxidants |
| spelling | doaj.art-ebc40163985843c995ef43d5ac66f84c2023-11-23T22:39:57ZengMDPI AGAntioxidants2076-39212022-10-011110205010.3390/antiox11102050Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident MacrophagesTao Yang0Qingguo Zhao1Meijun Hu2Simin Pan3Linying Zhang4Ruoxi Zhu5Bowen Zhou6Xuanhe Feng7Zhenhua Gao8Zhao Zhu9Yu Zhang10Liang Hu11Fei Liu12Zhaochen Shan13Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaDepartment of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USAOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaDepartment of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USADepartment of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USAOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaDepartment of Statistics, Texas A&M University, College Station, TX 77843, USAOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaDepartment of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USAOutpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, ChinaRadiotherapy 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.https://www.mdpi.com/2076-3921/11/10/2050sphingosine-1-phosphate signalingsalivary glandsirradiationhead and neck cancersendothelial cellsresident macrophages |
| spellingShingle | Tao Yang Qingguo Zhao Meijun Hu Simin Pan Linying Zhang Ruoxi Zhu Bowen Zhou Xuanhe Feng Zhenhua Gao Zhao Zhu Yu Zhang Liang Hu Fei Liu Zhaochen Shan Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages Antioxidants sphingosine-1-phosphate signaling salivary glands irradiation head and neck cancers endothelial cells resident macrophages |
| title | Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages |
| title_full | Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages |
| title_fullStr | Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages |
| title_full_unstemmed | Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages |
| title_short | Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages |
| title_sort | sphingosine 1 phosphate alleviates irradiation induced salivary gland hypofunction through preserving endothelial cells and resident macrophages |
| topic | sphingosine-1-phosphate signaling salivary glands irradiation head and neck cancers endothelial cells resident macrophages |
| url | https://www.mdpi.com/2076-3921/11/10/2050 |
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