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

Yang, Tao; Zhao, Qingguo; Hu, Meijuan; Pan, Simin; Zhang, Linying; Zhou, Bowen; Feng, Xuanhe; Gao, Zhenhua; Zhu, Zhenxin; Hu, Liang; Liu, Fei; Zhang, Shan

doi:10.3390/antiox11102050

Cited by 4 publications

(2 citation statements)

References 64 publications

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“…The enrichment of Trpm2 in Csf2r + resident macrophages might be an underlying mechanism for the high radiosensitivity of SMG rMΦs. Another possible mechanism is that IR rapidly damages SMG endothelial cells (Cotrim et al 2007), the major source of multiple factors essential for rMΦ homeostasis, including Cx3cl1 and Dhh reported here and a prosurvival lipid mediator, sphingosine-1-phosphate (S1P) (Yang et al 2022), which in turn contributes to the rapid decrease of SMG rMΦs. These data indicated that irradiation leads to a persistent decrease of salivary gland ILCs and their homeostatic paracrine interactions with Csf2r + resident macrophages, whereas transient Hedgehog activation after irradiation preserves these cells and their interactions.…”

Section: Resultsmentioning

confidence: 96%

A Salivary Gland Resident Macrophage Subset Regulating Radiation Responses

et al. 2023

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Radiotherapy of head and neck cancers frequently leads to irreversible hypofunction of salivary glands, which severely compromises the quality of life and is extremely difficult to treat. We found recently that salivary gland resident macrophages are sensitive to radiation and interact with epithelial progenitors and endothelial cells through homeostatic paracrine factors. Heterogeneous subpopulations of resident macrophages are present in other organs with distinct functions, whereas subpopulations of salivary gland resident macrophages with distinct functions or transcriptional profiles have not been reported yet. Using single-cell RNA sequencing, we found that mouse submandibular glands (SMGs) contain 2 distinct self-renewing resident macrophage subsets, an MHC-IIhi subset present in many other organs and an uncommon Csf2r+ subset. The main source of Csf2 in SMGs are innate lymphoid cells (ILCs) that rely on IL15 for maintenance, while the main source of IL15 protein is Csf2r+ resident macrophages, indicating a homeostatic paracrine interaction between these cells. Csf2r+ resident macrophages are the major source of hepatocyte growth factor (Hgf) that regulates homeostasis of SMG epithelial progenitors. Meanwhile, Csf2r+ resident macrophages are responsive to Hedgehog signaling that can rescue salivary function impaired by radiation. Consistently, irradiation persistently decreased numbers of ILCs and levels of IL15 and Csf2 in SMGs, which were all recovered by transient activation of Hedgehog signaling after radiation. Csf2r+ resident macrophages and MHC-IIhi resident macrophages share transcriptome profiles of perivascular macrophages and macrophages associated with nerves and/or epithelial cells in other organs, respectively, and such niche preferences were supported by lineage tracing and immunofluorescent staining. These findings reveal an uncommon resident macrophage subset that regulates the homeostasis of the salivary gland and is promising as the target to restore salivary gland function impaired by radiation.

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Section: Resultsmentioning

confidence: 96%

A Salivary Gland Resident Macrophage Subset Regulating Radiation Responses

et al. 2023

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“…When the radiation dose is increased to a certain extent, the expression of SSB1 is not increased but decreased, which may be caused by partial apoptosis and necrosis of cells, weakened repair ability and reduced SSB1 expression due to high dose radiation. The relative expression levels of SSB1 mRNA, SSB1 and NBS1 proteins in rat SMG cells were the highest at 1 h after a single dose of 2Gy irradiation, the dose was lower than those(10 Gy X-rays, HUVECs [61]; 15.0 Gy X rays, SMG-C6 cells [4]) reported in the literatures. Another study with human GBM cell line U87MG as the research object and DNA DSBs as the observation index found that the amount of DSBs in the cells irradiated with 2 Gy of iodine-131 was greater than the cells irradiated with 2 Gy of 6 MV X-ray.…”

Section: Discussionmentioning

confidence: 54%

Effect of silencing SSB1 gene on the expression of NBS1 in irradiated rat submandibular gland cells

Linjing Gao,

Qiuli Lv,

Yude Huang

et al. 2024

Cell Mol Biol (Noisy-le-grand)

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The salivary gland (SG) is a kind of organ vulnerable to ionizing radiation(IR). Radiotherapy is an important treatment for head and neck cancer, but in the process of radiotherapy, salivary gland cells will be injured by radiation to a certain extent. Ionising radiation-induced DNA double-strand break (IR-DSBs) is one of the most serious DNA damage. DNA repair proteins such as Nijmegen breakage syndrome protein 1 (NBS1) play a key role in the identification and repair of DNA damage, but the interaction between single-stranded DNAbinding protein 1(SSB1) and NBS1 has not been elucidated. In this study, we irradiated rat submandibular gland (SMG) cells, which were either infected with a rAdE5-SSB1-1p2-shRNA recombinant adenovirus to silence SSB or a control virus, to explore the effect of IR on the expression of NBS1 in the absence of SSB. Our results showed that the SSB1 mRNA transcripts and protein expression of SSB1 and NBS1 initially increased and decreased later with increased doses. The relative expression reached the highest levels when the SMG cells were irradiated with 2Gy of IR. Silencing the SSB1 gene suppressed the expression of both SSB1 and NBS1 regardless of irradiation. The expression of NBS1 decreased when the SSB1 gene was silenced. We concluded that IR affected the expression of both SSB1 and NBS1 and there is a synergistic effect on IR-induced NBS1 suppression and DSBs repair in SMG cells. These observations shed light on further investigation and elucidation of IR-caused DNA repair mechanisms.

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PANoptosis induced by inflammatory cytokines promotes salivary glands radiation injury

Qu,

Li,

Chen

et al. 2024

Oral Diseases

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ObjectiveSalivary glands are frequently damaged in patients undergoing radiotherapy for head and neck cancer. Whether PANoptosis, which is characterized by pyroptosis, apoptosis, and necroptosis, occurs during radiation injury to the salivary glands and its role remain unclear.Materials and MethodsRadiation‐induced injury models of mouse submandibular gland, as well as primary acinar cells and HSG cell lines were established to determine the presence of radiation‐induced PANoptosis. Several programmed cell death inhibitors, PFTα, disulfiram, Nec‐1 and zVAD, were used to compare the effects of different cell death pathway on radiation injury. The LEGENDplex™ Human Inflammation Panel was used to characterize the inflammatory landscape secreted by salivary gland cells after radiotherapy.ResultsSingle 15Gy or 8Gy radiotherapy triggered PANoptosis in mouse submandibular gland or salivary gland cells. Compared to the suppression of pyroptosis, apoptosis, or necroptosis alone, the inhibition of PANoptosis is more effective in preventing radiation injury to the salivary glands (p < 0.0001). The levels of multiple inflammatory cytokines were significantly up‐regulated in the supernatants of HSG cells within 48 h after IR. Neutralizing inflammatory cytokines are capable of inhibiting salivary glands PANoptosis.ConclusionsInhibition of PANoptosis induced by inflammatory cytokines can effectively prevent radiation injury of salivary glands.

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

Cited by 4 publications

References 64 publications

A Salivary Gland Resident Macrophage Subset Regulating Radiation Responses

A Salivary Gland Resident Macrophage Subset Regulating Radiation Responses

Effect of silencing SSB1 gene on the expression of NBS1 in irradiated rat submandibular gland cells

PANoptosis induced by inflammatory cytokines promotes salivary glands radiation injury

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