The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi

Ghasemzadeh, Mehran; Kaplan, Zane; Alwis, Imala; Schoenwaelder, Simone M.; Ashworth, Katrina; Westein, Erik; Hosseini, Ehteramolsadat; Salem, Haitham; Slattery, Robyn Maree; McColl, Shaun R.; Hickey, Michael J.; Ruggeri, Zaverio M.; Yao, Yuan; Jackson, Shaun P.

doi:10.1182/blood-2012-09-459636

Cited by 121 publications

(139 citation statements)

References 55 publications

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“…These data suggest similar inflammatory cascades may be initiated after painful WBV like in other neuropathic conditions. Only the chemokine CXCL7 decreases, but little is known about its role in pain; although it has been reported to recruit leukocytes, it also has actions different from prototypical chemokines [33,70]. Nonetheless, additional investigations are needed to understand its apparent discordant response to painful 8 Hz WBV.…”

Section: Discussionmentioning

confidence: 99%

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

Zeeman

Kartha

Jaumard

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Whole-body vibration (WBV) is associated with back and neck pain in military personnel and civilians. However, the role of vibration frequency and the physiological mechanisms involved in pain symptoms are unknown. Questions/purposes This study asked the following questions: (1) What is the resonance frequency of the rat spine for WBV along the spinal axis, and how does frequency of WBV alter the extent of spinal compression/ extension? (2) Does a single WBV exposure at resonance induce pain that is sustained? (3) Does WBV at resonance alter the protein kinase C epsilon (PKCe) response in the dorsal root ganglia (DRG)? (4) Does WBV at resonance alter expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn? (5) Does WBV at resonance alter the spinal neuroimmune responses that regulate pain? Methods Resonance of the rat (410 ± 34 g, n = 9) was measured by imposing WBV at frequencies from 3 to 15 Hz. Separate groups (317 ± 20 g, n = 10/treatment) underwent WBV at resonance (8 Hz) or at a nonresonant frequency (15 Hz). Behavioral sensitivity was assessed throughout to measure pain, and PKCe in the DRG was quantified as well as spinal CGRP, glial activation, and cytokine levels at Day 14. Results Accelerometer-based thoracic transmissibility peaks at 8 Hz (1.86 ± 0.19) and 9 Hz (1.95 ± 0.19, mean difference [MD] 0.290 ± 0.266, p \ 0.03), whereas the video-based thoracic transmissibility peaks at 8 Hz (1.90 ± 0.27), 9 Hz (2.07 ± 0.20), and 10 Hz (1.80 ± 0.25, MD 0.359 ± 0.284, p \ 0.01). WBV at 8 Hz produces more cervical extension (0.745 ± 0.582 mm, MD 0.242 ± 0.214, p \ 0.03) and compression (0.870 ± 0.676 mm, MD 0.326 ± 0.261, p \ 0.02) than 15 Hz (extension, 0.503 ± 0.279 mm; compression, 0.544 ± 0.400 mm). Pain is longer lasting (through Day 14) and more robust (p \ 0.01) after WBV at the resonant frequency (8 Hz) compared with 15 Hz WBV. PKCe in the nociceptors of the DRG increases according to the severity of WBV with greatest increases after 8 Hz WBV (p \ 0.03). However, spinal CGRP, cytokines, and glial activation are only evident after painful WBV at resonance. Conclusions WBV at resonance produces long-lasting pain and widespread activation of a host of nociceptive and neuroimmune responses as compared with WBV at a nonresonance condition. Based on this work, future investigations into the temporal and regional neuroimmune response to resonant WBV in both genders would be useful.

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Section: Discussionmentioning

confidence: 99%

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

Zeeman

Kartha

Jaumard

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…To gain insight into the mechanisms by which a-thrombin promotes leukocyte recruitment to sites of vascular injury, we utilized a traumatic needle injury model of endothelial perturbation in the mesenteric venous circulation of mice 30 . In this model, injury to the endothelium was associated with phosphatidylserine (PS) exposure on the cell surface ( Fig.…”

Section: Procoagulant Endothelial Cells Recruit Platelets and Leukocymentioning

confidence: 99%

“…We have therefore developed a microvascular traumatic needle injury model that results in localized endothelial injury in the mesenteric venous circulation, leading to thrombin generation, fibrin accumulation and a highly reproducible platelet and leukocyte recruitment response 30 . A key feature of this model is the ability to microinject pharmacological agents precisely at sites of platelet and leukocyte accumulation on the injured endothelium, which when combined with genetically manipulated mouse models, represents a potentially powerful approach to dissect the molecular pathways regulating intravascular leukocyte recruitment and trafficking.…”

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confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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“…These chemokines are important for neutrophil recruitment into rodents' lungs (9,34). CXCR2 also binds CXCL7, and both have been reported recently to promote leukocyte migration through thrombi (35).…”

mentioning

confidence: 99%

Platelet-Specific Chemokines Contribute to the Pathogenesis of Acute Lung Injury

Bdeir¹,

Gollomp²,

Stasiak

et al. 2017

Am J Respir Cell Mol Biol

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Platelets and neutrophils contribute to the development of acute lung injury (ALI). However, the mechanism by which platelets make this contribution is incompletely understood. We investigated whether the two most abundant platelet chemokines, CXCL7, which induces neutrophil chemotaxis and activation, and CXCL4, which does neither, mediate ALI through complementary pathogenic pathways. To examine the role of platelet-derived chemokines in the pathogenesis of ALI using Cxcl7 2/2 and Cxcl4 2/2 knockout mice and mice that express human CXCL7 or CXCL4, we measured levels of chemokines in these mice. ALI was then induced by acid aspiration, and the severity of injury was evaluated by histology and by the presence of neutrophils and protein in the bronchoalveolar lavage fluid. Pulmonary vascular permeability was studied in vivo by measuring extravasation of fluorescently labeled dextran. Murine CXCL7, both recombinant and native protein released from platelets, can be N-terminally processed by cathepsin G to yield a biologically active CXCL7 fragment. Although Cxcl7 2/2 mice are protected from lung injury through the preservation of endothelial/epithelial barrier function combined with impaired neutrophils transmigration, Cxcl4 2/2 mice are protected through improved barrier function without affecting neutrophils transmigration to the airways. Sensitivity to ALI is restored by transgenic expression of CXCL7 or CXCL4. Platelet-derived CXCL7 and CXCL4 contribute to the pathogenesis of ALI through complementary effects on neutrophil chemotaxis and through activation and vascular permeability.

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The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi

Abstract: Key Points Identification of a distinct leukocyte recruitment mechanism by platelet thrombi. Leukocyte migration through thrombi is partially mediated by one or more CXCR1/2 ligands, including NAP-2.

Cited by 121 publications

References 55 publications

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Platelet-Specific Chemokines Contribute to the Pathogenesis of Acute Lung Injury

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