CXC chemokine KC fails to induce neutrophil infiltration and neoangiogenesis in a mouse model of myocardial infarction

Oral, Hasan; Kanzler, Isabella; Tuchscheerer, Nancy; Curaj, Adelina; Simsekyilmaz, Sakine; Sönmez, Tolga Taha; Radu, Eugen; Postea, Otilia; Weber, Christian; Schuh, Alexander; Liehn, Elisa A.

doi:10.1016/j.yjmcc.2013.04.006

Cited by 26 publications

(17 citation statements)

References 32 publications

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“…This result is consistent with a previous study demonstrating no deficit in neutrophil recruitment to the CNS in cuprizone-fed mice with global ablation of Cxcr2 [30]. Additionally, another study demonstrated no change in the number of infiltrating neutrophils to sites of inflammation after administration of a CXCL1 inhibitor [55]. Therefore, CXCR2-mediated neutrophil migration is not implicated in EAE.…”

Section: Discussionsupporting

confidence: 92%

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Khaw

Cunningham

Tierney

et al. 2020

J Neuroinflammation

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Background: Multiple sclerosis (MS) is a chronic debilitating immune-mediated disease of the central nervous system (CNS) driven by demyelination and gray matter neurodegeneration. We previously reported an experimental autoimmune encephalomyelitis (EAE) MS mouse model with elevated serum CXCL1 that developed severe and prolonged neuron damage. Our findings suggested that CXCR2 signaling may be important in neuronal damage, thus implicating neutrophils, which express CXCR2 in abundance, as a potential cell type involved. The goals of this study were to determine if CXCR2 signaling in neutrophils mediate neuronal damage and to identify potential mechanisms of damage. Methods: EAE was induced in wild-type control and neutrophil-specific Cxcr2 knockout (Cxcr2 cKO) mice by repeated high-dose injections of heat-killed Mycobacterium tuberculosis and MOG 35-55 peptide. Mice were examined daily for motor deficit. Serum CXCL1 level was determined at different time points throughout disease development. Neuronal morphology in Golgi-Cox stained lumbar spinal cord ventral horn was assessed using recently developed confocal reflection super-resolution technique. Immune cells from CNS and lymphoid organs were quantified by flow cytometry. CNS-derived neutrophils were co-cultured with neuronal crest cells and neuronal cell death was measured. Neutrophils isolated from lymphoid organs were examined for expression of reactive oxygen species (ROS) and ROS-related genes. Thioglycolate-activated neutrophils were isolated, treated with recombinant CXCL1, and measured for ROS production. Results: Cxcr2 cKO mice had less severe disease symptoms at peak and late phase when compared to control mice with similar levels of CNS-infiltrating neutrophils and other immune cells despite high levels of circulating CXCL1. Additionally, Cxcr2 cKO mice had significantly reduced CNS neuronal damage in the ventral horn of the spinal cord. Neutrophils isolated from control EAE mice induced vast neuronal cell death in vitro when compared with neutrophils isolated from Cxcr2 cKO EAE mice. Neutrophils isolated from control EAE mice, but not Cxcr2 cKO mice, exhibited elevated ROS generation, in addition to heightened Ncf1 and Il1b transcription. Furthermore, recombinant CXCL1 was sufficient to significantly increase neutrophils ROS production. Conclusions: CXCR2 signal in neutrophils is critical in triggering CNS neuronal damage via ROS generation, which leads to prolonged EAE disease. These findings emphasize that CXCR2 signaling in neutrophils may be a viable target for therapeutic intervention against CNS neuronal damage.

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Section: Discussionsupporting

confidence: 92%

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Khaw

Cunningham

Tierney

et al. 2020

J Neuroinflammation

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“…Targeting CXCL8-CXCR1/2 axis has proved to be an effective approach to treat ischemic injury 203-205. Treatment with anti-CXCR2 antibody significantly blocked neutrophil infiltration into the infarcted area and reduced the size of infarction after long and delayed treatment in a mouse model of chronic myocardial infarction 206. Expression levels of CXCL5, macrophage migration-inhibitory factor (MIF) and CXCR2 were shown to be elevated in human atherosclerotic coronary artery.…”

Section: The Cxcl8-cxcr1/2 Axis In Inflammatory Diseasesmentioning

confidence: 99%

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

Ha¹,

Debnath²,

Neamati³

2017

Theranostics

577

464

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The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

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“…The molecular mechanisms identified were related to the abrogation of neutrophil inflammation, which has recently been implicated as a key pathophysiological process modulating atherosclerotic inflammation. More recently, the therapeutic potential of inhibiting CXCL1 with neutralizing antibodies was not confirmed in a mouse model of post-ischemic heart failure and remodeling [151], as these authors failed to observe any benefit different treatment schedules. This study therefore highlighted important limitations in the use of anti-chemokine drugs in atherosclerosis and their potential translation to human medicine.…”

Section: Selective Treatments Targeting Chemokinesmentioning

confidence: 99%

Immunological aspects of atherosclerosis

et al. 2013

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Atherosclerosis is a complex chronic inflammatory and metabolic disease that involves the collaboration of several cellular components of the immune system and results in thickening of the arterial wall. Atherosclerosis is also the primary cause of coronary artery and cerebrovascular diseases. A multitude of immune cell subsets, soluble molecules such as chemokines and cytokines, and circulating lipids play pivotal roles in atherosclerosis development. In this review, we highlight the role of the immune system in the course of atherosclerotic disease development and discuss the mechanisms involved.

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CXC chemokine KC fails to induce neutrophil infiltration and neoangiogenesis in a mouse model of myocardial infarction

Cited by 26 publications

References 32 publications

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

Immunological aspects of atherosclerosis

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