Hyperglycemia Impairs Neutrophil Mobilization Leading to Enhanced Metastatic Seeding

Fainsod-Levi, Tanya; Gershkovitz, Maya; Völs, Sandra; Kumar, Saran; Khawaled, Saleh; Sagiv, Jitka Yehudith; Sionov, Ronit Vogt; Grunewald, Myriam; Granot, Zvi

doi:10.1016/j.celrep.2017.11.010

Cited by 41 publications

(32 citation statements)

References 26 publications

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“…The expression of CXCR1/2 decreased after bariatric surgery in female adipose tissue [29]. Moreover, CXCR2deficient mice are resistant to diet-induced insulin resistance and diabetes, mainly because CXCL5 blocks insulin signaling in muscle by activating the muscle Jak/STAT/SOCS pathway through the CXCR2 receptor [30]. In accordance with this finding, our RNA-seq analysis revealed that the CXCR1 and CXCR2 genes were significantly upregulated in patients with type 2 diabetes compared with healthy controls.…”

Section: Discussionsupporting

confidence: 82%

Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

Lin

Zhou

Wang

et al. 2020

Journal of Diabetes Research

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Aim. There are increasing evidence demonstrating that neutrophil-mediated inflammation plays a role in the etiology of type 2 diabetes. However, the molecular mechanisms by which neutrophils contribute to type 2 diabetes remain largely unknown. The aim of the present work was to identify possible changes in circulating neutrophils to better elucidate neutrophil involvement in human type 2 diabetes. Methods. Patients newly diagnosed with type 2 diabetes (n=5) and age- and sex-matched healthy controls (n=5) were recruited. Neutrophils were purified from type 2 diabetes patients and controls, and RNA sequencing (RNA-seq) was used for comprehensive transcriptome analysis. Differentially expressed genes (DEGs) were screened, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. Real-time polymerase chain reaction (qPCR) was used for validation in external samples of type 2 diabetes patients (n=8) and healthy controls (n=8). Results. Gene expression analysis showed that, compared with neutrophils from healthy controls, there were 1990 upregulated DEGs and 1314 downregulated DEGs in neutrophils from type 2 diabetes patients. GO analysis demonstrated that the DEGs were mainly involved in myeloid leukocyte activation, T cell activation, adaptive immunity, and cytokine production. The top 20 enriched KEGG pathways included the cytokine-cytokine receptor interaction pathway, NF-κB signaling pathway, cell adhesion molecules, and chemokine signaling pathway. Furthermore, qPCR of genes related to neutrophil activation revealed that the expression of SELL, SELP, CXCR1, and S100A8 was significantly increased in neutrophils from type 2 diabetes patients compared with that in neutrophils from controls. Conclusions. Our study reveals an abnormal activation of circulating neutrophils at the transcriptome level in type 2 diabetes patients. These findings suggest a potential involvement of neutrophil dysfunction in the pathologic process of type 2 diabetes and provide insight into potential therapeutic targets for type 2 diabetes.

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Section: Discussionsupporting

confidence: 82%

Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

Lin

Zhou

Wang

et al. 2020

Journal of Diabetes Research

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“…Thirdly, immune cell activation and dysfunction have been described in COPD, atherosclerosis and T2D, and linked with adverse disease outcomes (figure 1c). Clearly, neutrophils are not the only cell that show altered functionality in these three diseases, but the fact that neutrophil dysfunction occurs in COPD, atherosclerosis and T2D may provide novel links between these diseases [22,42,43]. This cellular dysfunction may represent a physiological response to a pathological event, but there is increasing evidence that chronic inflammation (as seen in COPD, atherosclerosis and T2D) can contribute to a shift in immune cell phenotype or subpopulation, changing the cell's usual response to an inflammatory insult, and increasing the potential for damage ( figure 1c).…”

Section: An Overview Of Mechanisms For Multimorbiditymentioning

confidence: 99%

“…While neutrophils are not the only cells that play a role in COPD, atherosclerosis and T2D, they are the most abundant immune cells found in lung secretions of patients diagnosed with COPD and their products have been shown to cause all facets of lung disease in animal and cell models (from chronic bronchitis to emphysema); correlating with disease severity and decline [19,20]. Recent advances in imaging technologies have also identified that neutrophils are present in the lipid core of human plaques and neutrophilia correlates with the number of rupture-prone lesions [21] and, although less studied, diabetic patients, rats and mice clearly demonstrate consistent defects of neutrophil chemotactic, phagocytic and microbicidal activities [22]. Together, this suggests neutrophils may provide a link between these three disease areas.…”

Section: Introductionmentioning

confidence: 99%

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

2020

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Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting.

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“…At the inflammation site, neutrophils display a variety of functional responses ranging from phagocytosis and respiratory burst to the extracellular release of their granule contents, which includes proteases and other microbicidal molecules as well as granule protein embedded DNA traps (NETosis) . However, growing evidence suggests a crucial regulatory role for neutrophils in tumor establishment and progression . Recent studies also document the morphological and functional heterogeneity among TANs and their association with protumor or antitumor responses depending on the TME they are part of .…”

Section: Introductionmentioning

confidence: 99%

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

SenGupta

Subramanian

Parent

2018

Journal of Leukocyte Biology

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The directed migration of neutrophils to sites of injury or infection is mediated by complex networks of chemoattractant‐receptor signaling cascades. The recent appreciation of neutrophils as active participants in tumor progression and metastasis has drawn attention to a number of chemokine‐receptor systems that may drive their recruitment to tumors. However, the dynamic nature of the tumor microenvironment (TME) along with the phenotypic diversity among tumor‐associated neutrophils (TANs) call for a more comprehensive approach to understand neutrophil trafficking to tumors. Here, we review recent advances in understanding how guidance cues underlie neutrophil migration to primary and secondary tumor sites. We also discuss how the presence of other myeloid cells, such as functionally diverse subsets of tumor‐associated macrophages (TAMs), can further influence neutrophil accumulation in tumors. Finally, we highlight the importance of hypoxia sensing in localizing TAMs and TANs in the tumor niche and provide a cohesive view on how both myeloid cell types shape TME‐associated extracellular matrix organization, which in turn contribute to tumor progression.

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Hyperglycemia Impairs Neutrophil Mobilization Leading to Enhanced Metastatic Seeding

Cited by 41 publications

References 26 publications

Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

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