Project Title: Investigating the cell intrinsic metabolism of conventional dendritic cells and identifying whether this is altered in adipose tissues.
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
Aim 1: Define the metabolome of lymphoid and white adipose tissue conventional dendritic cells
Recent advances in our understanding of the immune system have led scientists to realise that, in order to respond to differences in stimuli within their local environments, immune cells must alter their metabolism to meet functional demands. Among immune cells, dendritic cells are a crucial component of the immune system, bridging the innate and adaptive immune responses. To date the majority of immune cell metabolism research has focused on cells in non-adipose tissues and conventional dendritic cell research has remained somewhat neglected. However, recent studies have indicated that in adipose tissues, where there is increased abundance of carbon sources such as lipids, immune cells could utilise different metabolic pathways and thus function differently. This project aims to fully characterise metabolic profiles of conventional dendritic cells in lymphoid and white adipose tissue, before establishing the role these metabolic pathways could play in disease.
Diseases such as obesity are now appreciated to have a significant inflammatory component, characterised, in the case of obesity, by chronic low grade inflammation. With adipose tissues being abundantly present throughout the body and commonly located adjacent to almost every major organ, it is crucial to gain an understanding of the immune system in adipose tissues, as they could play a significant role in a plethora of diseases. This importance is only increased by the fact that obesity is increasing in incidence and is now a recognised major contributor to the onset of cancer, as well as other diseases such as atherosclerosis.
Preliminary data in the Longhi group show that certain genes associated with fatty acid oxidation and oxidative phosphorylation are upregulated specifically in adipose tissues when compared to lymphoid and non-lymphoid tissues, which share similar expression fingerprints. It was also found that culturing non adipose tissue conventional dendritic cells (cDCs) underneath adipose tissue increased their oxygen consumption compared to cells cultured normally. These cDCs were also able to promote a stronger T cell response, when stimulated with TLR4 ligand GLA, compared to cDCs cultured without adipose tissue. This indicates that adipose tissue has properties which serve to alter conventional dendritic cell metabolism and function.
To better understand the metabolism utilised by cDCs in vivo we will carry out metabolomics in order to identify the frequency at which metabolites are present in spleen and white adipose tissue cDCs. From this we will validate any significant differences with functional and biochemical assays. Together this will provide us with a mechanistic understanding of how metabolism is altered in cDCs in white adipose tissue compared to in other tissues, as well as aid future investigation into how these cells could be manipulated therapeutically.
Aim 2: Investigate the role of the serine metabolism in conventional dendritic cells
A growing body of work in the literature has begun to unravel the mechanistic underpinnings of mitochondrial metabolism and glycolysis in immune cells. By comparison relatively little is understood on a mechanistic level about serine metabolism. Serine metabolism has been shown to be important in feeding the folate cycle and methionine cycle, with crucial roles in purine synthesis for nucleotide generation, as well as generation of antioxidant gluthathione. Serine metabolism also generates alpha-ketogluturate for the TCA cycle and NADPH for maintaining cells redox potential.
Unpublished data in the Bianchi group has shown that IKKe is a crucial activator of serine metabolism and this induced serine metabolism has important roles in macrophage activation.
Recent advances in our understanding of the immune system have led scientists to realise that, in order to respond to differences in stimuli within their local environments, immune cells must alter their metabolism to meet functional demands. Among immune cells, dendritic cells are a crucial component of the immune system, bridging the innate and adaptive immune responses. To date the majority of immune cell metabolism research has focused on cells in non-adipose tissues and conventional dendritic cell research has remained somewhat neglected. However, recent studies have indicated that in adipose tissues, where there is increased abundance of carbon sources such as lipids, immune cells could utilise different metabolic pathways and thus function differently. This project aims to fully characterise metabolic profiles of conventional dendritic cells in lymphoid and white adipose tissue, before establishing the role these metabolic pathways could play in disease.
Diseases such as obesity are now appreciated to have a significant inflammatory component, characterised, in the case of obesity, by chronic low grade inflammation. With adipose tissues being abundantly present throughout the body and commonly located adjacent to almost every major organ, it is crucial to gain an understanding of the immune system in adipose tissues, as they could play a significant role in a plethora of diseases. This importance is only increased by the fact that obesity is increasing in incidence and is now a recognised major contributor to the onset of cancer, as well as other diseases such as atherosclerosis.
Preliminary data in the Longhi group show that certain genes associated with fatty acid oxidation and oxidative phosphorylation are upregulated specifically in adipose tissues when compared to lymphoid and non-lymphoid tissues, which share similar expression fingerprints. It was also found that culturing non adipose tissue conventional dendritic cells (cDCs) underneath adipose tissue increased their oxygen consumption compared to cells cultured normally. These cDCs were also able to promote a stronger T cell response, when stimulated with TLR4 ligand GLA, compared to cDCs cultured without adipose tissue. This indicates that adipose tissue has properties which serve to alter conventional dendritic cell metabolism and function.
To better understand the metabolism utilised by cDCs in vivo we will carry out metabolomics in order to identify the frequency at which metabolites are present in spleen and white adipose tissue cDCs. From this we will validate any significant differences with functional and biochemical assays. Together this will provide us with a mechanistic understanding of how metabolism is altered in cDCs in white adipose tissue compared to in other tissues, as well as aid future investigation into how these cells could be manipulated therapeutically.
Aim 2: Investigate the role of the serine metabolism in conventional dendritic cells
A growing body of work in the literature has begun to unravel the mechanistic underpinnings of mitochondrial metabolism and glycolysis in immune cells. By comparison relatively little is understood on a mechanistic level about serine metabolism. Serine metabolism has been shown to be important in feeding the folate cycle and methionine cycle, with crucial roles in purine synthesis for nucleotide generation, as well as generation of antioxidant gluthathione. Serine metabolism also generates alpha-ketogluturate for the TCA cycle and NADPH for maintaining cells redox potential.
Unpublished data in the Bianchi group has shown that IKKe is a crucial activator of serine metabolism and this induced serine metabolism has important roles in macrophage activation.
| Description | School Visit (Bromley/SE London) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | I travelled to a High school and hosted a workshop/presentation to around 30 12 year olds. Predominanltly my session was based around what it is like to work in medical research, and I also used fun activities to explain the concept of mass spectrometry, and activities looking at H and E stained images to try and identify what healthy sections look like compared to disease. I also took several questions over the 2 hour workshop. The pupils were all engaged and expressed interest in the work, some students also said they wanted to work in research one day. Feedback from my the Director of Sciecne at the school also said students were talking positively about the session for days afterwards. I also showed them online resources and games they could play if they wanted to explore more about the topics covered. |
| Year(s) Of Engagement Activity | 2020 |