The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates

Uddin, Mohib; Betts, Catherine J.; Robinson, Ian; Malmgren, Anna; Humfrey, Charles

doi:10.3324/haematol.2016.152371

Cited by 14 publications

(8 citation statements)

References 14 publications

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“…AZD5069 (AstraZeneca) is a selective CXCR2 antagonist that has been tested for safety and efficacy in pre-clinical and clinical studies of COPD and asthma (O'Byrne et al, 2016;Pedersen et al, 2018). AZD5069 was able to block neutrophil trafficking while preserving neutrophilmediated host immunity (Jurcevic et al, 2015;Uddin et al, 2017). The administration of AZD5069 reduced NETopathic inflammation of sputum neutrophils from patients with COPD (Pedersen et al, 2018;Uddin et al, 2019).…”

Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

et al. 2020

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There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.

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Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

et al. 2020

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“…Anti-CXCR2 blockade can negate multiple features of pulmonary neutrophilic inflammation in vivo , supporting a pro-inflammatory role for CXCR2 signaling (118). AZD5069 is a selective CXCR2 antagonist developed by AstraZeneca that blocks neutrophil trafficking without hindering neutrophil effector responses of host defense (119, 120). Recently, AZD5069 has been shown to diminish CXCR2-mediated neutrophil infiltrates in spontaneous sputum from bronchiectasis patients (69% inhibition) (121), as well as pronounced reduction in induced sputum and bronchial biopsies from patients with more severe asthma (90% inhibition) (122).…”

Section: Cxcr2 Signaling In Severe Asthmamentioning

confidence: 99%

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

et al. 2019

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Neutrophils play a central role in innate immunity, inflammation, and resolution. Unresolving neutrophilia features as a disrupted inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD) and severe asthma. The extent to which this may be linked to disease pathobiology remains obscure and could be further confounded by indication of glucocorticoids or concomitant respiratory infections. The formation of neutrophil extracellular traps (NETs) represents a specialized host defense mechanism that entrap and eliminate invading microbes. NETs are web-like scaffolds of extracellular DNA in complex with histones and neutrophil granular proteins, such as myeloperoxidase and neutrophil elastase. Distinct from apoptosis, NET formation is an active form of cell death that could be triggered by various microbial, inflammatory, and endogenous or exogenous stimuli. NETs are reportedly enriched in neutrophil-dominant refractory lung diseases, such as COPD and severe asthma. Evidence for a pathogenic role for respiratory viruses (e.g., Rhinovirus), bacteria (e.g., Staphylococcus aureus) and fungi (e.g., Aspergillus fumigatus) in NET induction is emerging. Dysregulation of this process may exert localized NET burden and contribute to NETopathic lung inflammation. Disentangling the role of NETs in human health and disease offer unique opportunities for therapeutic modulation. The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. NET-stabilizing agents using CXCR2 antagonists are being investigated in proof-of-concept studies in patients with COPD to provide mechanistic insights. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.

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“…In this study, we used AZD5069 to modulate recruitment of TAN into tumor lesions in vivo . AZD5069 is a small molecule antagonist with over 100-fold selectivity for CXCR2 relative to CXCR1 receptor, that does not adversely affect neutrophil-mediated host immunity (31, 32). Beyond a potential immuno-oncological target (20), AZD5069 has been extensively studied as an orally active immunotherapy in chronic respiratory diseases, including COPD (33, 34), bronchiectasis (35) and severe asthma (36, 37).…”

Section: Introductionmentioning

confidence: 99%

Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions

Sody

Uddin

Grüneboom³

et al. 2019

Front. Immunol.

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Across a majority of cancer types tumor-associated neutrophils (TAN) are linked with poor prognosis. However, the underlying mechanisms, especially the intratumoral behavior of TAN, are largely unknown. Using intravital multiphoton imaging on a mouse model with neutrophil-specific fluorescence, we measured the migration of TAN in distinct compartments of solid tumor cell lesions in vivo . By longitudinally quantifying the infiltration and persistence of TAN into growing tumors in the same animals, we observed cells that either populated the peripheral stromal zone of the tumor (peritumoral TAN) or infiltrated into the tumor core (intratumoral TAN). Intratumoral TAN showed prolonged tumor-associated persistence and reduced motility compared to peritumoral TAN, whose velocity increased with tumor progression. Selective pharmacological blockade of CXCR2 receptors using AZD5069 profoundly inhibited recruitment of TAN into peritumoral regions, while intratumoral infiltration was only transiently attenuated and rebounded at later time points. Our findings unravel distinct spatial dynamics of TAN that are partially and differentially regulated via the CXCR2 signaling pathway.

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The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates

Cited by 14 publications

References 14 publications

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions

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