3 results on '"Adam T. Braithwaite"'
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2. Divergent Roles for TRAIL in Lung Diseases
- Author
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Adam T. Braithwaite, Helen M. Marriott, and Allan Lawrie
- Subjects
TRAIL ,TNF-related apoptosis-inducing ligand ,pulmonary arterial hypertension ,immune regulation ,pulmonary vascular disease ,pulmonary fibrosis ,Medicine (General) ,R5-920 - Abstract
The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a widely expressed cytokine that can bind five different receptors. TRAIL has been of particular interest for its proposed ability to selectively induce apoptosis in tumour cells. However, it has also been found to regulate a wide variety of non-canonical cellular effects including survival, migration and proliferation via kinase signalling pathways. Lung diseases represent a wide range of conditions affecting multiple tissues. TRAIL has been implicated in several biological processes underlying lung diseases, including angiogenesis, inflammation, and immune regulation. For example, TRAIL is detrimental in pulmonary arterial hypertension—it is upregulated in patient serum and lungs, and drives the underlying proliferative pulmonary vascular remodelling in rodent models. However, TRAIL protects against pulmonary fibrosis in mice models—by inducing apoptosis of neutrophils—and reduced serum TRAIL is found in patients. Conversely, in the airways TRAIL positively regulates inflammation and immune response. In COPD patients and asthmatic patients challenged with antigen, TRAIL and its death receptors are upregulated in serum and airways. Furthermore, TRAIL-deleted mouse models have reduced airway inflammation and remodelling. In the context of respiratory infections, TRAIL assists in immune response, e.g., via T-cell toxicity in influenza infection, and neutrophil killing in S. pneumoniae infection. In this mini-review, we examine the functions of TRAIL and highlight the diverse roles TRAIL has in diseases affecting the lung. Disentangling the facets of TRAIL signalling in lung diseases could help in understanding their pathogenic processes and targeting novel treatments.
- Published
- 2018
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3. Rapid neutrophil mobilisation by VCAM-1+ endothelial extracellular vesicles
- Author
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Naveed, Akbar, Adam T, Braithwaite, Emma M, Corr, Graeme J, Koelwyn, Coen, van Solingen, Clément, Cochain, Antoine-Emmanuel, Saliba, Alastair, Corbin, Daniela, Pezzolla, Malene, Møller Jørgensen, Rikke, Bæk, Laurienne, Edgar, Carla, De Villiers, Mala, Gunadasa-Rohling, Abhirup, Banerjee, Daan, Paget, Charlotte, Lee, Eleanor, Hogg, Adam, Costin, Raman, Dhaliwal, Errin, Johnson, Thomas, Krausgruber, Joey, Riepsaame, Genevieve E, Melling, Mayooran, Shanmuganathan, Christoph, Bock, David R F, Carter, Keith M, Channon, Paul R, Riley, Irina A, Udalova, Kathryn J, Moore, Daniel, Anthony, and Robin P, Choudhury
- Abstract
Acute myocardial infarction rapidly increases blood neutrophils (2 hours). Release from bone marrow, in response to chemokine elevation, has been considered their source, but chemokine levels peak up to 24 hours after injury, and after neutrophil elevation. This suggests that additional non-chemokine-dependent processes may be involved. Endothelial cell (EC) activation promotes the rapid (30 minutes) release of extracellular vesicles (EVs), which have emerged as an important means of cell-cell signalling and are thus a potential mechanism for communicating with remote tissues.Here, we show that injury to the myocardium rapidly mobilises neutrophils from the spleen to peripheral blood and induces their transcriptional activation prior to arrival at the injured tissue. Time course analysis of plasma EV composition revealed a rapid and selective increase in EVs bearing VCAM-1. These EVs, which were also enriched for miRNA-126, accumulated preferentially in the spleen where they induced local inflammatory gene and chemokine protein expression, and mobilised splenic-neutrophils to peripheral blood. Using CRISPR/Cas9 genome editing we generated VCAM-1-deficient EC-EVs and showed that its deletion removed the ability of EC-EVs to provoke the mobilisation of neutrophils. Furthermore, inhibition of miRNA-126 in vivo reduced myocardial infarction size in a mouse model.Our findings show a novel EV-dependent mechanism for the rapid mobilisation of neutrophils to peripheral blood from a splenic reserve and establish a proof of concept for functional manipulation of EV-communications through genetic alteration of parent cells.Peripheral blood neutrophils are rapidly elevated following acute myocardial infarction (AMI) and prior to alterations in systemic cytokines. Extracellular vesicles (EVs) are membrane enclosed particles that carry protein and miRNAs and are rapidly liberated from endothelial cells (EC). Here, we show that following AMI EC-derived-EVs (EC-EVs) mediate neutrophil mobilisation from the spleen via EC-EV-VCAM-1 and induce transcriptional activation of neutrophils in the blood to favour miRNA-126-mRNA targets; miRNA-126 antagomir treatment lowers infarct size. EC-EV-VCAM-1 and EC-EV-miRNA-126 are novel mechanisms that mobilise splenic reserve of neutrophils, a previously unidentified source of neutrophils in sterile ischaemic injury.
- Published
- 2021
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