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Pulmonary Staphylococcus aureus infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation.

ABSTRACT: The formation of neutrophil extracellular traps (NETs) was recently identified as one of the most important processes for the maintenance of host tissue homeostasis in bacterial infection. Meanwhile, pneumonia infection has a poor effect on cancer patients receiving immunotherapy. Whether pneumonia-mediated NETs increase lung metastasis remains unclear. In this study, we identified a critical role for multidrug-resistant Staphylococcus aureus infection-induced NETs in the regulation of cancer cell metastasis. Notably, S. aureus triggered autophagy-dependent NETs formation in vitro and in vivo and increased cancer cell metastasis. Targeting autophagy effectively regulated NETs formation, which contributed to the control of cancer metastasis in vivo. Moreover, the degradation of NETs by DNase I significantly suppresses metastasis in lung. Our work offers novel insight into the mechanisms of metastasis induced by bacterial pneumonia and provides a potential therapeutic strategy for pneumonia-related metastasis.

SUBMITTER: Qi JL

PROVIDER: S-EPMC8491238 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Pulmonary <i>Staphylococcus aureus</i> infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation.

Qi Jia-Long JL He Jin-Rong JR Liu Cun-Bao CB Jin Shu-Mei SM Gao Rui-Yu RY Yang Xu X Bai Hong-Mei HM Ma Yan-Bing YB

MedComm 20200730 2

The formation of neutrophil extracellular traps (NETs) was recently identified as one of the most important processes for the maintenance of host tissue homeostasis in bacterial infection. Meanwhile, pneumonia infection has a poor effect on cancer patients receiving immunotherapy. Whether pneumonia-mediated NETs increase lung metastasis remains unclear. In this study, we identified a critical role for multidrug-resistant <i>Staphylococcus aureus</i> infection-induced NETs in the regulation of ca ...[more]

PMID: 34766117

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Project description:BackgroundTo investigate the effect and mechanism of Celastrol on the formation of neutrophil extracellular traps (NETs), and to provide a theoretical basis for the clinical application of Tripterygium wilfordii.MethodsFirst, we isolated neutrophils from the peripheral blood of healthy volunteers, and then observed the effect of Celastrol on Phorbol Myristate Acetate (PMA)-induced neutrophil release of NETs. The level of NETs was detected by using the membrane-impermeable nucleic acid dye, SytoxGreens. In addition, the levels of reactive oxygen species (ROS) were also examined to determine whether Celastrol affects ROS production during PMA-induced NETs.ResultsCelastrol produced significant cytotoxicity at a concentration of 5 µM (213.2±75.07), and the effect of stimulant PMA (25 nM) treatment was not statistically different (197.3±25.15) (P=0.9167). Celastrol (1.25, 0.625, and 0.3125 µM) did not exhibit cytotoxicity when treating neutrophils. Compared with the PMA (25 nM) + Celastrol (1.25, 0.625, and 0.3125 µM) group and the PMA (25 nM) monotherapy group, SytoxGreen showed a statistically significant reduction in fluorescence at 528 µM under 485 µM light excitation. Also, under the co-localization marker of Hochest and SytoxGreen double staining, we observed that the release of NETs in the PMA-treated group was higher than that in the control group. The PMA-induced neutrophil release of NETs was markedly reduced compared to the PMA-treated group. The NET release was substantially decreased under double staining with the Hochest and SytoxGreen co-localization markers. The fluorescence intensity of the Celastrol plus PMA group was significantly lower than that of the PMA treatment group alone, indicating a decrease in the level of intracellular ROS. Interestingly, the level of ROS in the treatment group who received Celastrol alone was lower than that in the control group, indicating that Tripterygium wilfordii could inhibit the spontaneous production of ROS by neutrophils in the absence of stimulation.ConclusionsThe molecular mechanism of Celastrol involves inhibition of PMA-stimulated neutrophil NETs formation in vitro, which is possibly related to the reduction of ROS levels. This indicates that Celastrol, the main component in Tripterygium wilfordii, can inhibit the formation of NETs, which provides a theoretical basis for the study of NETs-related diseases.

Project description:The formation of neutrophil extracellular traps (NETs) is an immune defense mechanism of neutrophilic granulocytes. Moreover, it is also involved in the pathogenesis of autoimmune, inflammatory, and neoplastic diseases. For that reason, the process of NET formation (NETosis) is subject of intense ongoing research. In vitro approaches to quantify NET formation are commonly used and involve neutrophil stimulation with various activators such as phorbol 12-myristate 13-acetate (PMA), lipopolysaccharides (LPS), or calcium ionophores (CaI). However, the experimental conditions of these experiments, particularly the media and media supplements employed by different research groups, vary considerably, rendering comparisons of results difficult. Here, we present the first standardized investigation of the influence of different media supplements on NET formation in vitro. The addition of heat-inactivated (hi) fetal calf serum (FCS), 0.5% human serum albumin (HSA), or 0.5% bovine serum albumin (BSA) efficiently prevented NET formation of human neutrophils following stimulation with LPS and CaI, but not after stimulation with PMA. Thus, serum components such as HSA, BSA and hiFCS (at concentrations typically found in the literature) inhibit NET formation to different degrees, depending on the NETosis inducer used. In contrast, in murine neutrophils, NETosis was inhibited by FCS and BSA, regardless of the inducer employed. This shows that mouse and human neutrophils have different susceptibilities toward the inhibition of NETosis by albumin or serum components. Furthermore, we provide experimental evidence that albumin inhibits NETosis by scavenging activators such as LPS. We also put our results into the context of media supplements most commonly used in NET research. In experiments with human neutrophils, either FCS (0.5-10%), heat-inactivated (hiFCS, 0.1-10%) or human serum albumin (HSA, 0.05-2%) was commonly added to the medium. For murine neutrophils, serum-free medium was used in most cases for stimulation with LPS and CaI, reflecting the different sensitivities of human and murine neutrophils to media supplements. Thus, the choice of media supplements greatly determines the outcome of experiments on NET-formation, which must be taken into account in NETosis research.

Dataset Information

Pulmonary Staphylococcus aureus infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation.

Publications

Pulmonary <i>Staphylococcus aureus</i> infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation.

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