David Greaves

Macrophages – In the Greaves Laboratory we study macrophage biology. Macrophages are cells of the innate immune system found in virtually every tissue in the body. Originally it was thought that all tissue resident macrophages were derived from circulating white blood cells called monocytes. For some macrophage-like cells such as dendritic cells in the large intestine this remains true, but we now appreciate that most of the macrophages we find in tissues were seeded during foetal life and are maintained by self-renewal. We can recognise macrophages in tissues by using antibodies that recognise macrophage expressed proteins such as F4/80 or CD68. Work in the Greaves Lab has used the gene regulatory elements of the human CD68 gene to drive reporter gene expression that allows us to follow migration and persistence within different tissues.

Phagocytosis – One of the most fascinating aspects of macrophage cell biology is the way these immune cells reorganise their cytoskeleton to engulf large particles such as bacteria, yeast particles, even dead and dying cells of the same size. In the Greaves Lab we use a wide range of techniques to study macrophage phagocytosis. In recent work we have shown that a membrane protein expressed on the surface of macrophages at sites of inflammation called GPR84 can enhance macrophage phagocytosis of different ‘phagocytic meals’. With our collaborators in the Department of Chemistry we are synthesising and testing a range of small molecules that bind and activate the GPR84 receptor to increase macrophage phagocytosis.

Drug repurposing – Inflammation is a driver of human disease and an unmet clinical need exists for new and better anti-inflammatory medicines. Because macrophages are a key cell type in the pathology of both acute and chronic inflammatory disease, they are an appealing therapeutic target for developing anti-inflammatory medicines. Drug repurposing, the use of existing medicines for new indications, is an attractive and pragmatic strategy for the discovery of novel anti-inflammatory medicines. In the Greaves Lab we have set out to identify novel drug repurposing candidates with anti-inflammatory activity in macrophages by looking for inhibition of macrophage NF-κB activity. We are currently studying FDA approved medicines that inhibit NF-kB activity in macrophages and reduce inflammatory cytokine production in tissue culture and in animal models of acute inflammation.

Chemical Biology – Chemical Biology uses chemistry to perturb and investigate biological systems often by creating small molecules to probe living cells and organisms. For nearly 15 years I have been working with Professor Angela Russell in the Departments of Chemistry and Pharmacology to study G protein-coupled receptors (GPCRs) expressed by innate immune cells such as the cannabinoid CB2 receptor and the orphan receptor GPR84. Highlights of our collaboration are the demonstration that anti-inflammatory effects of the CB2 receptor in vivo are mediated through reduction of neutrophil recruitment to sites of inflammation (Kapellos TS, Taylor L et al. FASEB Journal 2019) and generation of a wide range of synthetic small molecules that can activate the orphan GPR84 receptor (Wang P et al. J Med Chem 2024). We are currently looking to develop chemical tool compounds to localise GPCRs in cells and tissues and study other immuno-metabolic receptors including FFAR4.

The Greaves Lab is a potential host laboratory for graduate students on the British Heart Foundation (BHF) Cardiovascular Science (Vascular Rewind) programme

Applications are to be submitted via the Graduate Admissions Portal:  DPhil in Cardiovascular Science (VascularRewind)

Further details can be found on the MSD Course page and FindAPhD