Heat-killed salmonella typhimurium (HKST) protects mice against radiation in TLR4-dependent manner

Xu, Yang; Chen, Yuanyuan; Liu, Hu; Xiao, Lanbo; Guo, Jiaming; Cao, Kang; Liu, Cong; Li, Bailong; Cai, Jianming; Ju, Jin-tao; Gao, Fu; Yang, Yue

doi:10.18632/oncotarget.17859

Cited by 16 publications

(13 citation statements)

References 23 publications

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“…In previous immunological studies, it has been reported that HKST effectively activates TLR2 and TLR4, and activates TLR5 at high concentration with its flagellin . Our previous study found HKST significantly inhibited radiation‐induced cell apoptosis, increased cell survival and alleviated DNA damage, and we found that TLR4 is more significant for the radioprotective effects of HKST by using knockout mice and siRNA model, meanwhile, the protective effects of HKST is partially dependent on TLR2 . In this study, we demonstrated that HKST effectively mitigated radiation injury and inflammation in lung tissues.…”

Section: Introductionsupporting

confidence: 54%

“…The latest research showed that CBLB502, a TLR5 agonist derived from Salmonella flagellin , effectively protected mammalian haematopoietic and gastrointestinal systems from acute irradiation syndrome . Our previous studies have also proved that activation of TLR2 and TLR4 significantly protected mice and cultured cells against ionizing radiation. However, the expression levels of different TLRs in distinct cells in lung tissues are greatly varied, and different types of TLRs initiate different downstream pathways, so we assume that the activation of multiple TLRs can exert a broader radiation protection effect in RILI.…”

Section: Introductionmentioning

confidence: 87%

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Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

Cao

Luo²,

Leiyuan³

et al. 2019

Clin Exp Pharma Physio

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Radiation‐induced lung injury (RILI) is a serious complication in thoracic tumour radiotherapy. It often occurs in clinical chest radiotherapy and acute whole‐body irradiation (WBI) caused by nuclear accidents or nuclear weapon attack. Some radioprotective agents have been reported to exert protective effects when given prior to radiation exposure, however, there is no treatment strategy available for preventing RILI. In this study, we demonstrated that heat‐killed Salmonella typhimurium (HKST), a co‐agonist of Toll‐like receptors 2 (TLR2), Toll‐like receptors 4 (TLR4) and Toll‐like receptors 5 (TLR5), mitigated radiation‐induced lung injury through the transforming growth factor‐β (TGF‐β) signalling pathway. We found that HKST alleviated lung hyperaemia and pathological damage after irradiation, indicated that HKST inhibits the early inflammatory reaction of radiation‐induced lung injury. Then, for the first time, we observed HKST reduced collagen deposit induced by irradiation in the later phase (7‐14 week) of RILI, and we found that HKST inhibited radiation‐induced cell apoptosis in lung tissues. We found that HKST reduced the level of TGF‐β and regulated its downstream signalling pathway. Finally, it was found that HKST inhibited radiation‐induced epithelial–mesenchymal transition (EMT) in lung tissues. In conclusion, our data showed that HKST effectively mitigated RILI through regulating TGF‐β, provide novel treatment strategy for RILI in whole‐body irradiation and radiotherapy.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 87%

Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

Cao

Luo²,

Leiyuan³

et al. 2019

Clin Exp Pharma Physio

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“…Previous study have shown that the pretreatment with attenuated Salmonwlla typhimurium could induce protective cell-mediated immunity or facilitate the conversion of immunosuppressive myeloid-derived suppressor cells into TNF-α-secreting neutrophil-like myeloid cells thereby protecting mice against malaria or tumor [17,18]. In our preliminary work, damages on bone marrow, spleen and testis which were induced by γ-irradiation could be signi cantly eased by the pretreatment of HKST [19]. However, the radio-protective effects of HKST on small intestine has remained unclear.…”

Section: Introductionmentioning

confidence: 65%

Heat Killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway

Chen

Cao

et al. 2020

Preprint

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Purpose: Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) appears to be a limited factor in radiotherapy and a great threat for soldiers on nuclear-related military missions. However, there are currently no approved medical strategies to effectively prevent or mitigate the damage on intestine induced by IR. The present study aimed to elucidate the protective activity of Heat Killed Salmonella typhimurium (HKST) on intestine against ionizing radiation exposure. Materials and Methods: Mouse intestinal crypts and intestinal organoids were isolated from C57BL/6J mice. Mice and HIEC cells were exposed to 60Co γ‐radiation. The dosage was set as following: whole body radiation of 8 Gy; mouse intestinal organoids were irradiated with 0 Gy, 4 Gy, and 6 Gy of γ-rays at dose rate of 1 Gy/min. Cells or mice were pretreated with Heat Killed Salmonella typhimurium (HKST) (107 cells/mice) at 12 hours prior to irradiation.Results: By culturing mouse intestinal organoids and employing whole body irradiation of mice, we found that the radiation-induced damage on intestine was dramatically mitigated by pretreating with HSKT in vitro and in vivo, in which the structure of intestinal organoids and small intestine of the HKST-treated group was more integrated than of the radiation damage group, and HKST pretreatment remarkably promoted the proliferation of intestinal cells post IR exposure (Figure 1 and 2). Further study showed that the radio-protective effects of HKST was involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radio-protective effects of HKST. Conclusion: Our study demonstrated that Heat Killed Salmonella typhimurium (HKST) could significantly alleviate the damage on intestine induced by IR, and the radio-protective effect of HKST was depended on DDR mediated by Wnt signaling pathway. These findings demonstrated that HKST is a potential bacterium using for the prevention of IR-induced GI toxicity in clinical practice.

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“…Currently, several TLRs ligands have been proved to exert radioprotective effects, for example, CBLB502 for TLR5, CpG-ODN for TLR9, LPS for TLR4 and CBLB613 for TLR2/6 etc. Our group also demonstrated that Heat-Killed Salmonella typhimurium and Heat-Killed Mycobacterium tuberculosis protected mice against radiation through TLR signaling pathways [ 16 , 17 ]. These findings shed new lights for application of TLR ligand in clinics.…”

Section: Discussionmentioning

confidence: 99%

Monophosphoryl lipid a attenuates radiation injury through TLR4 activation

et al. 2017

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Ionizing radiation causes severe damage to human body, and normal tissue toxicity in cancer radiotherapy also limits its further application. It is urgently required to develop safe and effective radioprotector. Our previous study has shown that toll like receptor 4 (TLR4) was dispensable for basal radiation resistance. However, severe toxicity of its traditional agonist lipopolysaccharide limits the clinical application. In present study, we demonstrated that monophosphoryl lipid A (MPLA), a potent TLR4 agonist with low toxicity, effectively attenuated radiation injury on in vitro and in vivo. MPLA increased cell survival and inhibited cell apoptosis after irradiation, and cell cycle arrest was also inhibited. Radiosensitive tissues including spleen, intestine, bone marrow and testis were protected from radiation damages in a TLR4 dependent manner. We also found that myeloid differentiation factor 88 (MyD88) accounted more than Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) for the radioprotective effects of MPLA. In conclusion, our finding suggests TLR4 agonist MPLA as a safe and effective radioprotector for clinical application.

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Heat-killed salmonella typhimurium (HKST) protects mice against radiation in TLR4-dependent manner

Cited by 16 publications

References 23 publications

Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

Heat Killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway

Monophosphoryl lipid a attenuates radiation injury through TLR4 activation

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