Luke C DaviesSwansea University | SWAN
Luke C Davies
Doctor of Philosophy
About
54
Publications
14,595
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3,439
Citations
Citations since 2017
Introduction
Additional affiliations
May 2015 - April 2019
May 2014 - April 2015
Education
September 2010 - March 2014
September 2006 - August 2009
Publications
Publications (54)
Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cell...
Introduction
Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an...
Background
Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells, namely T cells, have also been regularly observed, which appear to play a crucial role in the long-term host respo...
Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (C...
Introduction
Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity.
A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immu...
Aim
Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells have also been regularly observed, which appear to play a crucial role in the long-term host response. This study investig...
The physiological shifts during pregnancy predispose women to a ten-fold higher risk of developing sepsis, a life-threatening condition characterised by a maladapted host-response to infection. We present a comprehensive synthesis of maternal immunity during pregnancy, addressing whether altered set-points in immune homeostasis lower the tipping po...
The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (T regs), yet how the microbiota-T reg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E 2 (PGE 2), a well-known mediator of inflammation, inhib...
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dy...
The Coronavirus infectious disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a world health concern and can cause severe disease and high mortality in susceptible groups. While vaccines offer a chance to treat disease, prophylactic and anti-viral treatments are still of vital importance,...
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dy...
The Coronavirus infectious disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a world health concern and can cause severe disease and high mortality in susceptible groups. While vaccines offer a chance to treat disease, prophylactic and anti-viral treatments are still of vital importance,...
Background:
Mesh implants are widely used to reinforce the abdominal wall, although the inevitable inflammatory foreign body reaction (FBR) at the interface leads to complications. Macrophages are suspected to regulate the subsequent scar formation, but it is still unclear whether adequate fibrous scar formation with collagen deposition depends ma...
[This corrects the article DOI: 10.1016/j.omtm.2019.10.004.].
Implants like meshes for the reinforcement of tissues implement the formation of a persistent inflammation with an ambient fibrotic reaction. In the inflammatory infiltrate several distinct cell types have been identified, but CD68+ macrophages are supposed to be most important. To investigate the collaboration among the various cell types within t...
Oxylipins are potent mediators requiring strict control. How they are removed en masse during infection/inflammation is unknown. Herein, lipopolysaccharide (LPS) dynamically increased their mitochondrial b-oxidation, impacting leukocyte bioactivity. Genetic/pharmacological targeting of CPT1 showed <50 oxylipins were robustly removed by macrophage m...
The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg crosstalk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits m...
The alarm cytokine interleukin-1β (IL-1β) is a potent activator of the inflammatory cascade following pathogen recognition. IL-1β production typically requires two signals: first, priming by recognition of pathogen-associated molecular patterns leads to the production of immature pro-IL-1β; subsequently, inflammasome activation by a secondary signa...
Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13C tracing and mitochondrial respiration exper...
Tissue-resident macrophages exhibit specialized phenotypes dependent on their in vivo physiological niche. Investigation of their function often relies upon complex whole mouse transgenic studies. While some appropriate lineage-associated promoters exist, there are no options for tissue-specific targeting of macrophages. We have developed full prot...
Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including...
Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit⁺ neutrophils subsets can engage in oxidative mitocho...
Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation—key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils—heterogeneous cell populations possessing cell and...
Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset-specific metabolites in situ, especially in the tumor setting. Here, we determine how a macrophage-specific metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show peritoneal tumors (B...
Classical pro-inflammatory activation of macrophages is characterized by profound intracellular metabolic changes, with increased glycolytic usage of carbon, away from Oxidative Phosphorylation (OXPHOS). We previously demonstrated that Nitric Oxide (NO) levels induced in Bone Marrow Derived Macrophages (BMDMs) from Wild Type (WT) mice are necessary...
Neutrophils are a vital component of the immune system, however in cancer they often play major roles in tumour progression, partly by generating reactive oxygen species (ROS) which disrupts lymphocyte function. Metabolically, neutrophils are often overlooked as purely glycolytic, however we show that immature subsets, defined by c-Kit expression,...
The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in gl...
Background:
If treatment with intravenous steroids fail, inflammatory bowel disease patients with acute severe colitis face systemic anti-tumor necrosis factor biologic rescue therapy or colectomy. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on...
Supplementary material
Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, “alternatively activated” macr...
Supporting Information
The inflammatory activation and recruitment of defined myeloid populations is essential for controlling the bridge between innate and adaptive immunity and shaping the immune response to microbial challenge. However, these cells exhibit significant functional heterogeneity and the inflammatory signals that differentially influence their effector ch...
Macrophages have been at the heart of immune research for over a century and are an integral component of innate immunity. Macrophages are often viewed as terminally-differentiated monocytic phagocytes. They infiltrate tissues during inflammation, and form polarized populations that perform pro- or anti-inflammatory functions. Tissue resident macro...
Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche–specific functions. Many populations self-renew
independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional
profile for the major self-renewing population of peritoneal macrophages in mice. Th...
Aristolochic acid nephropathy is characterized by rapidly progressive tubulointerstitial nephritis culminating in end-stage renal failure and urothelial malignancy. Profibrotic effects of aristolochic acid are linked to growth arrest of proximal tubular epithelial cells; however, the underlying mechanisms are largely undetermined. miRNAs are small,...
Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Re...
The general paradigm is that monocytes are recruited to sites of inflammation and terminally differentiate into macrophages. There has been no demonstration of proliferation of peripherally-derived inflammatory macrophages under physiological conditions. Here we show that proliferation of both bone marrow-derived inflammatory and tissue-resident ma...
In this Viewpoint, we concentrate on the aspects of macrophage biology that we believe are fundamental for an appropriate contextual understanding of macrophage function during acute inflammation. These are the different origins of macrophage populations (and the implications of this for the renewal of these populations in the adult); and the impac...
Macrophage (MØ) biology is routinely modelled in the peritoneal cavity, a vascular tissue readily infiltrated by leukocytes during inflammation. After several decades of study, no consensus has emerged regarding the importance of in situ proliferation versus peripheral monocyte recruitment for the maintenance of tissue resident MØs. By applying spe...
We have examined the potential to generate bona fide macrophages (MØ) from conditionally immortalised murine bone marrow precursors. MØ can be derived from Hoxb8 conditionally immortalised macrophage precursor cell lines (MØP) using either M-CSF or GM-CSF. When differentiated in GM-CSF (GM-MØP) the resultant cells resemble GM-CSF bone marrow-derive...
Projects
Project (1)
General research questions: How are immune cells equipped with a 'free-pass' to enter and survive in many different types of tissue? How do immune cells ignore or adapt to complex tissue environments that vary in growth factors, oxygen, metabolites and cytokines? How does immune cell interference influence tissue function? These broad research questions will drive the project, however the perfect model in which to address these has not yet been identified - this requires a broad collaborative network, assembly of a multidisciplinary team and acquisition of significant funding.
