Publications by authors named "David R Greaves"

Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a coordinated and precise manner. Here, we investigate the origin and transcriptional reprogramming of monocytes using a model of acute inflammation, zymosan-induced peritonitis. Monocyte trafficking and adoptive transfer experiments confirmed that monocytes undergo rapid phenotypic change as they exit the blood and give rise to monocyte-derived macrophages that persist during the resolution of inflammation.

View Article and Find Full Text PDF

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions.

View Article and Find Full Text PDF

Inflammation is a driver of human disease and an unmet clinical need exists for new anti-inflammatory medicines. As a key cell type in both acute and chronic inflammatory pathologies, macrophages are an appealing therapeutic target for anti-inflammatory medicines. Drug repurposing - the use of existing medicines for novel indications - is an attractive strategy for the identification of new anti-inflammatory medicines with reduced development costs and lower failure rates than de novo drug discovery.

View Article and Find Full Text PDF
Article Synopsis
  • BTK is a special protein that helps control inflammation in certain immune cells called macrophages, and it also seems to affect how fat-related immune cells work, especially in people with obesity and diabetes.
  • When researchers blocked BTK in mice, it helped them stay healthier on a high-fat diet by improving how their bodies process sugar.
  • This means that targeting BTK could be a new way to help reduce inflammation and treat problems related to being overweight, making it an important discovery for health.
View Article and Find Full Text PDF

GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons.

View Article and Find Full Text PDF

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via G/cAMP and β-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure-activity relationship (SAR) analysis.

View Article and Find Full Text PDF

GPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that phenocopy the response of primary cells in a label-free cell electrical impedance (CEI) sensing system that measures cell morphology and adhesion.

View Article and Find Full Text PDF

Inflammatory responses are crucial for controlling infections and initiating tissue repair. However, excessive and uncontrolled inflammation causes inflammatory disease. Processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 depend on caspase-1 activation within inflammasomes.

View Article and Find Full Text PDF

Drug repurposing is an attractive, pragmatic approach to drug discovery that has yielded success across medical fields over the years. The use of existing medicines for novel indications enables dramatically reduced development costs and timescales compared with drug discovery and is therefore a promising strategy in cardiovascular disease, where new drug approvals lag significantly behind that of other fields. Extensive evidence from pre-clinical and clinical studies show that chronic inflammation is a driver of pathology in cardiovascular disease, and many efforts have been made to target cardiovascular inflammation therapeutically.

View Article and Find Full Text PDF

Current genetic tools designed to target macrophages often target cells from all myeloid lineages. Therefore, we sought to generate a novel transgenic mouse which has a tamoxifen inducible Cre-recombinase under the control of the human CD68 promoter (hCD68-CreERT2). To test the efficiency and specificity of the of Cre-recombinase activity we crossed the hCD68-CreERT2 mice with a loxP-flanked STOP cassette red fluorescent protein variant (tdTomato) mouse.

View Article and Find Full Text PDF

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS).

View Article and Find Full Text PDF

Background And Purpose: Bruton's TK (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation and survival of leukaemic cells in B-cell malignancies. However, BTK is expressed in myeloid cells, particularly neutrophils, monocytes and macrophages where its inhibition has been reported to cause anti-inflammatory properties.

Experimental Approach: We explored the role of BTK on migration of myeloid cells (neutrophils, monocytes and macrophages), in vitro using chemotaxis assays and in vivo using zymosan-induced peritonitis as model systems.

View Article and Find Full Text PDF
Article Synopsis
  • Macrophages are important cells in our immune system that help with inflammation and healing, and they also help in developing organs like the heart.
  • In a study, researchers found that macrophages are found in certain areas of the developing heart, and they interact with tiny blood vessels called lymphatics.
  • When there were not enough macrophages, the heart's blood vessels got messed up, showing that these cells are super important for the heart to grow and develop properly.
View Article and Find Full Text PDF

Macrophage chemotaxis is crucial during both onset and resolution of inflammation and unique among all leukocytes. Macrophages are able to switch between amoeboid and mesenchymal migration to optimise their migration through 3D environments. This subtle migration phenotype has been underappreciated in the literature, with macrophages often being grouped and discussed together with other leukocytes, possibly due to the limitations of current chemotaxis assays.

View Article and Find Full Text PDF

We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene in mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation ("cytokine storm") induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis , changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome.

View Article and Find Full Text PDF

GPR84 is an inflammation-induced receptor highly expressed on immune cells, yet its endogenous ligand is still unknown. This makes any interpretation of its physiological activity difficult. However, experiments with potent synthetic agonists have highlighted what the receptor can do, namely, enhance proinflammatory signaling and macrophage effector functions such as phagocytosis.

View Article and Find Full Text PDF

Background And Purpose: There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity.

Experimental Approach: Using an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation.

View Article and Find Full Text PDF
Article Synopsis
  • Macrophages play a critical role in cardiac repair after a heart attack by modifying the extracellular matrix and activating fibroblasts for collagen production.
  • Research shows that macrophages not only help initiate scar formation but also directly contribute collagen to the scar tissue through a process demonstrated in both zebrafish and mice.
  • This study challenges the traditional view that collagen deposition is solely the responsibility of myofibroblasts, indicating that macrophages are significant players in the fibrotic response following heart injury.
View Article and Find Full Text PDF

Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines. A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury.

View Article and Find Full Text PDF

GPR84 is an orphan G-protein-coupled receptor that is expressed on immune cells and implicated in several inflammatory diseases. The validation of GPR84 as a therapeutic target is hindered by the narrow range of available chemical tools and consequent poor understanding of GPR84 pathophysiology. Here we describe the discovery and characterization of DL-175, a potent, selective, and structurally novel GPR84 agonist and the first to display significantly biased signaling across GPR84-overexpressing cells, primary murine macrophages, and human U937 cells.

View Article and Find Full Text PDF

In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored.

View Article and Find Full Text PDF
Article Synopsis
  • Cannabinoid receptors (CB) are immune cell-localized receptors that may regulate inflammation, but their exact anti-inflammatory mechanisms remain unclear.
  • Research using a mouse model showed that mice lacking CB had increased recruitment of neutrophils and monocytes in response to inflammation, with elevated levels of certain inflammatory markers.
  • The findings indicate that the enhanced inflammatory response in CB-deficient mice is due to intrinsic changes in neutrophils, suggesting that targeting CB could be a potential strategy for developing new anti-inflammatory treatments.
View Article and Find Full Text PDF

Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria. To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung.

View Article and Find Full Text PDF

Inducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth of Mycobacterium tuberculosis (M.tb), presumably via nitric oxide (NO) mediated killing. Here we show that leukocyte-specific deficiency of NO production, through targeted loss of the iNOS cofactor tetrahydrobiopterin (BH4), results in enhanced control of M.

View Article and Find Full Text PDF

Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal.

View Article and Find Full Text PDF