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

Ha, Helen; Debnath, Bikash; Neamati, Nouri

doi:10.7150/thno.15625

Cited by 554 publications

(523 citation statements)

References 475 publications

(357 reference statements)

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“…In line with these findings, in our study, blocking CXCR2 with SB225002 exerted a negative effect on EPC migration toward MSCs in vitro and in vivo. CXCR1 and CXCR2 are closely related receptors sharing 76% sequence homology, and they can both recognize CXC chemokines present in MSC‐CM, such as CXCL6 and CXCL8 (27). However, unlike endothelial cells, where CXCR1 and CXCR2 knockdown with shRNAs showed significant and parallel decrease in cell migration (28), CXCR1 blockade only marginally affected EPC migration toward MSCs.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Yang

Yin

et al. 2018

FASEB j.

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Tissue-engineered constructs (TECs) hold great promise for treating large bone defects. Incorporated mesenchymal stem cells (MSCs) can facilitate the vascularization of TECs. Nevertheless, the underlying mechanism remains ambiguous. Here we analyzed the roles of C-X-C chemokine receptor 2 (CXCR2) and its downstream signal pathways in MSC-induced endothelial progenitor cell (EPC) migration. Transwell assays and immunofluorescence staining were performed for cell migration analysis in vitro and in vivo, respectively. A series of signal inhibitors and short hairpin RNA was used for screening essential signaling molecules. We found that blockade of CXCR2 abolished the migration of EPCs toward MSCs as well as subsequent vascularization and bone repair in TECs. Moreover, screening results suggested that steroid receptor coactivator (Src) acted as a predominant downstream effector of CXCR2. Further molecular biologic and histomorphological experiments revealed that the action of Src required the phosphorylation of ras-related C3 botulinum toxin substrate 1 (Rac1), which was pivotal for the development of lamellipodia and filopodia. The phosphorylation and colocalization of paxillin kinase linker (PKL) and vav guanine nucleotide exchange factor 2 (Vav2) were essential for the activation of Rac1. Therefore, we demonstrated that MSCs promoted EPC migration via activating CXCR2 and its downstream Src-PKL/Vav2-Rac1 signaling pathway. These findings unveiled the molecular mechanism in the vascularization of TECs and were expected to provide novel targets for efficacy improvement.-Li, Z., Yang, A., Yin, X., Dong, S., Luo, F., Dou, C., Lan, X., Xie, Z., Hou, T., Xu, J., Xing, J. Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue-engineered constructs via activating CXCR2-Src-PKL/Vav2-Rac1.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Yang

Yin

et al. 2018

FASEB j.

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“…The seeded biochip channel was treated with chemokine (20 n m ), chemokine peptide (50 n m ; Peptide 1, Peptide 2 or Peptide 3); or low‐molecular‐weight heparin, tinzaparin (50 n m ; Leo Pharmaceuticals, Ballerup, Denmark), to analyse their potential role in displacing the chemokine from GAG . In parallel, different CXCR1/2 antagonists [repertaxin (Cayman Chemical, Cambridge, UK) and SB225002 (SML0716; Sigma‐Aldrich)], and CXCR2 antagonist SB265610 (SML0421; Sigma‐Aldrich) were used at 50 n m – to analyse their role in displacing the chemokine from GPCR – treating neutrophils before the assay. A 10‐μl treatment was inserted into each channel, followed by careful addition of 40 μl of the treatment on to each channel reservoir.…”

Section: Methodsmentioning

confidence: 99%

A C‐terminal CXCL8 peptide based on chemokine–glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation

et al. 2019

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Summary Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G‐protein‐coupled receptors (GPCRs). In addition, chemokines interact with cell‐surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine interleukin‐8/CXCL8, a prototypical neutrophil chemoattractant, is characterized by a long, highly positively charged GAG‐binding C‐terminal region, absent in most other chemokines. To examine whether the CXCL8 C‐terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesized the wild‐type CXCL8 C‐terminal [CXCL8 (54–72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface plasmon resonance showed that Peptide 1, corresponding to the core CXCL8 GAG‐binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8‐induced calcium signalling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8‐induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil‐mediated inflammation based on modulation of chemokine–GAG binding.

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“…By intravenously injecting Evans blue, we could monitor the vascular permeability to the site of inflammation [42]. Acetic acid causes peritoneal inflammation and induces an increase in PGE 2 and PGF 2a in the peritoneal fluid [43]. This capillary permeability assay is a typical model for acute phase of inflammation, where mediators of inflammation released following stimulation lead to the dilation of both arterioles and venules and increase capillary permeability [24].…”

Section: Discussionmentioning

confidence: 99%

“…However, uncontrolled inflammation induces various diseases in humans, including asthma, rheumatoid arthritis, and cancer [2]. The hallmark of initial inflammation is increased vascular permeability, blood flow, and leukocytosis at the injured tissue site [3].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effect of <i>o</i>-Vanillic Acid on Lipopolysaccharide-Stimulated Macrophages and Inflammation Models

Lee¹,

Lee²,

Shin³

et al. 2018

JFNR

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Inflammation is an important biological reaction in the body in response to external stimuli. Excessive inflammation causes various inflammatory disorders such as allergic hypersensitivity, autoimmune disease, rheumatoid arthritis, and cancer. Macrophages play a major role in the inflammatory response by producing inflammatory mediators such as nitric oxide, prostaglandin E 2 , and pro-inflammatory cytokines. Natural products are often a source of bioactive compounds, which have great potential as novel therapeutic agents. Amomum xanthoides extract has been shown to possess various pharmacological activities including anti-inflammatory activity. This study evaluated the anti-inflammatory potential of o-vanillic acid (o-VA), a major compound in A. xanthoides, using lipopolysaccharide (LPS)-induced macrophages and in vivo animal models. o-VA decreased, in a concentration-dependent manner, the LPS-induced gene expression and production of inflammatory mediators, such as inducible nitric oxidase/cyclooxygenase-2 and pro-inflammatory cytokines, by reducing the nuclear factor-κB activation. In addition, o-VA dose-dependently ameliorated acetic acid-induced vascular permeability and zymosan-induced leukocyte migration. Thus, we suggest that o-VA can be used as a pharmacological agent or food supplement in the treatment of inflammatory conditions.

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

Cited by 554 publications

References 475 publications

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

A C‐terminal CXCL8 peptide based on chemokine–glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation

Anti-Inflammatory Effect of <i>o</i>-Vanillic Acid on Lipopolysaccharide-Stimulated Macrophages and Inflammation Models

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