Granulocyte colony-stimulating factor (G-CSF) increases histone-complexed DNA plasma levels in healthy volunteers

Schoergenhofer, Christian; Schwameis, Michael; Wohlfarth, Philipp; Brostjan, Christine; Abrams, Simon T.; Toh, Cheng‐Hock; Jilma, Bernd

doi:10.1007/s10238-016-0413-6

Cited by 16 publications

(12 citation statements)

References 30 publications

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“…We did not find a sex difference in the number of neutrophils in the blood following rG-CSF treatment in naïve mice. This finding is in contrast to clinical findings in healthy volunteers; Schoergenhofer et al (2017) identified more plasma neutrophil histone-complexed DNA in the men compared to women after a single of rG-CSF. Consistent with our previous reports in the 4NQO model (Scheff et al, 2018), there is a sex difference in neutrophil infiltration in saline-treated mice with HSC-3 tumors.…”

Section: Discussioncontrasting

confidence: 89%

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

Scheff

Alemu

Klares

et al. 2019

Front. Mol. Neurosci.

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Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

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Section: Discussioncontrasting

confidence: 89%

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

Scheff

Alemu

Klares

et al. 2019

Front. Mol. Neurosci.

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“…G-CSF treatment in humans has been associated with the elevation of markers of systemic NET formation (47) and increased G-CSF levels have been previously correlated with NET-associated microthrombosis in cancer patients (17, 27). More recently, biomarkers of the systemic formation of NETs were associated with the occurrence of venous thromboembolism in certain cancer types (18).…”

Section: Discussionmentioning

confidence: 99%

IL-1β Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model

et al. 2019

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Cancer patients are at increased risk of developing thrombosis, comorbidity that has been associated with increased neutrophil counts and the formation of neutrophil extracellular traps (NETs). Interleukin-1β (IL-1β) modulates the expression of granulocyte colony-stimulating factor (G-CSF), a cytokine that promotes cancer-associated neutrophilia and NET generation. Herein, we combined a murine breast cancer model with a flow-restriction thrombosis model to evaluate whether the IL-1β blockade could interfere with cancer-associated thrombosis. Mice bearing metastatic 4T1 tumors exhibited high neutrophil counts as well as elevated expression of G-CSF and IL-1β in their tumors. On the other hand, mice bearing non-metastatic 67NR tumors showed no elevation in neutrophil counts and displayed low expression levels of G-CSF and IL-1β in their tumors. 4T1 tumor-bearing mice but not 67NR tumor-bearing mice exhibited a NET-dependent prothrombotic state. Pharmacological blockade of IL-1 receptor (IL-1R) decreased the primary growth of 4T1 tumors and reduced the systemic levels of myeloperoxidase, cell-free DNA (cfDNA) and G-CSF, without interfering with the neutrophil counts. Most remarkably, the blockade of IL-1R abolished the prothrombotic state observed in 4T1 tumor-bearing mice. Overall, our results demonstrate that IL-1β might be a feasible target to attenuate cancer-associated thrombosis, particularly in cancer types that rely on increased G-CSF production and involvement of NET formation.

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“…NETs cause platelet aggregation, thrombin activation, and fibrin clot formation (64). Building upon these observations, since administration of G-CSF to healthy volunteers increases NET levels (65), one possible hypothesis is that G-CSF use in HCT recipients may predispose to or perpetuate TA-TMA, though to date there are no data analyzing this potential risk factor. Fungal infections, especially aspergillus, have been linked to TA-TMA (6, 16), possibly mediated via the same pathway by which the angioinvasion process leads to endothelial activation.…”

Section: Risk Factorsmentioning

confidence: 99%

Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management

2019

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (e.g., permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA “triad” of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase (LDH). While not diagnostic, this triad should prompt further evaluation for TA-TMA. There is increased understanding of the risk factors for the development of TA-TMA, including those which are inherent (e.g., race, genetics), transplant approach-related (e.g., second HCT, use of HLA-mismatched donors), and related to post-transplant events (e.g., receipt of calcineurin inhibitors, development of graft-vs. -host-disease, or certain infections). This understanding should lead to enhanced screening for TA-TMA signs and symptoms in high-risk patients. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a pro-coagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. This has led to the formulation of a “Three-Hit Hypothesis” in which patients with either an underlying predisposition to complement activation or pre-existing endothelial injury (Hit 1) undergo a toxic conditioning regimen causing endothelial injury (Hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (Hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury. Finally, several intriguing approaches to TA-TMA prophylaxis have been identified. Future work on the development of a single diagnostic test with high specificity and sensitivity, and the development of a robust risk-scoring system, will further improve the management of this serious post-transplant complication.

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Granulocyte colony-stimulating factor (G-CSF) increases histone-complexed DNA plasma levels in healthy volunteers

Cited by 16 publications

References 30 publications

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

IL-1β Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model

Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management

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