Inflammation, Metabolism and My Inflamed Left Foot

martin-hornshaw · ‎07-01-2016

Tumor, rubor, calor and dolor at the Metabolomics Society Meeting in Dublin

Dublin. It's not just about Guinness.

Here I am at the Metabolomics Society annual meeting in Dublin along with nearly 900 other people as I write this. Metabolomics is a rapidly growing scientific discipline dedicated to the comprehensive measurement and characterisation of the small molecule metabolites in biological systems such as cell, tissue or organism. Using metabolomics, the accurate, steady-state physiology of a cell or organism and its responses to changes to its environment can be measured. Causes of change could be many, for example, in response to the presence of a drug, infection or environmental contaminant and metabolomics can help us to understand the metabolism which underpins the biology of that cell or organism. Understanding biology is essential to understanding the mechanisms underlying disease.

Prof Luke O'Neill

I want to tell you about one lecture that had a strong impact on me. Prof Luke O’Neill of Trinity Biomedical Sciences Institute at Trinity College Dublin only had to walk a few minutes from his lab to give his plenary lecture and for once not have to travel half way around the world. And it wasn’t even raining! Entitled ‘The intersection between inflammation and metabolism,' I was in for a real education and an enjoyable hour.

My inflamed left foot

Inflammation is an essential response of body tissues to harmful stimuli such as pathogens and damaged cells. It is protective and involves immune cells, blood cells and what are known as molecular mediators such as cytokines. The purpose of inflammation is to remove the cause of the cell injury, to remove the cells damaged by the initial cause or by the inflammation itself and to start to repair that damage. You have certainly had an inflammation somewhere or other. It would be amazing if you hadn’t. Last week my left foot showed the four classic signs – swelling, redness, heat and pain (the rather lovely sounding ‘tumor, rubor, calor and dolor’; the four acute signs of inflammation identified by Celsus two thousand years ago) and I have no idea why. I took a photo but I don't think I will share that with you. Who wants to see my inflamed left foot?

Too little inflammation is a bad thing as it could lead to progressive destruction of, for example, infected tissue, while too much inflammation can lead to a whole raft of inflammatory diseases. This takes me back to Prof O’Neill’s talk.

Inflammatory diseases

I was surprised by some of the diseases he listed as being inflammatory. The usual ones were there such as rheumatoid arthritis, osteoarthritis, asthma, multiple sclerosis and Crohn’s disease (and many more) but he also included Alzheimer’s and Parkinson’s diseases. Of particular interest was the context for his study of inflammation; that many of these diseases currently have ineffective treatments or the only treatments are basically to relieve the symptoms. With inflammatory disease there is a great deal of unmet medical need.

Metabolism

He described for us more or less the above, that inflammatory diseases result from unwanted inflammation after inflammatory gene expression, resulting from signals such as cytokines but he posed a question I had never thought of: 'Do these inflammatory diseases actually result from disturbances in metabolism?’ Following the tissue damage or infection innate immune receptors are triggered and these receptors change metabolism.

NLRP3 is the key

It would take quite some time to describe Prof O'Neill's excellent lecture and I would have to get into a fair amount of detail but if I may, I will try to summarise some of the key findings described. He has studied the macrophage for many years, which is the key cell in inflammation. The macrophage phagocytoses (swallows/engulfs) the offending item causing the inflammatory response.

He and his team and collaborators have studied a key gene, NLRP3, that has an essential role in inflammation as a sensor of pathogens and Prof O’Neill has been testing a small molecule drug that might well help to treat inflammatory disease. It is called MCC-950 and is a highly selective inhibitor of NLRP3. Over-expression of its protein (or mutation of the NLRP3 gene) stimulates the cytokine IL-1β which causes inflammation (it is proinflammatory). He described for us several animal disease models of, for example, multiple sclerosis, Alzheimer’s disease and Parkinson’s disease, where symptoms improved upon treatment with MCC-950 after the drug reduced levels of IL-1β. Thus we have a potential therapeutic, a tool to investigate diseases caused by NLRP3 and also an indication that there is a common underlying mechanism involved in these different diseases.

Metabolism changes during inflammation

During inflammation there is a massive change in metabolism. The inflammatory macrophage is metabolically rewired. For example, succinate and citrate levels (intermediates in the tricarboxylic cycle) increase significantly and if you block glycolysis in the macrophage then it will become anti-inflammatory. In collaboration with the Broad Institute Prof O’Neill used metabolomics to study the metabolism of the macrophage. They used liquid chromatography-mass spectrometry (LC-MS) to uncover changes in metabolism and gene arrays to study changes of expression of genes in inflammation. They found many changes in metabolism and of particular note the level of succinate increased 30-fold.

Metformin to reduce inflammation?

Prof O’Neill had a lot more to say and all of it was fascinating. His work on metformin (an anti-diabetes drug) and anti-inflammatory reprogramming was just as interesting. Someone in the audience asked if we should all be taking metformin for our health, which question I found intriguing. Prof O’Neill advised against so perhaps it is not a panacea. I think for now we will need to watch this space and see what happens.

Metabolomics as a tool for therapeutic intervention

In short, Prof O’Neill asked can we exploit metabolism and metabolic plasticity to treat inflammatory disease. Metabolic plasticity means that the metabolism can recover if some metabolic pathway is affected. Can we selectively knock down some aspect of metabolism which is involved in inflammation without causing any unwanted side-effect and treat illness? Can we use metabolomics to find potential therapeutic interventions?

Metabolomics: it's not just for experts

Prof O’Neill collaborated with metabolomics experts but this field is becoming more user-friendly with, in particular, the software needed to process the data generated in metabolomics becoming more and more powerful and easy-to-use. It is up to companies like Thermo Fisher Scientific to develop tools to enable future metabolomics research. I think that we are doing that.

Metabolomics data challenges are being successfully addressed

Issues in metabolomics have been, for example, correctly identifying unknown metabolites of interest. The mzCloud advanced mass spectral database has been developed to address this. Every day high resolution/accurate mass MS/MS and MSⁿ spectra of new metabolites, drugs, industrial chemicals, etc are being added to the mzCloud database to help interpret metabolomics data and data from other fields. Compound Discoverer 2.0 is a new software platform used to identify the changes in metabolism caused by perturbation, such as the inflammation described above, or perhaps the effect of a drug on the cell and so on.

Metabolomically hopeful

As ever I am hopeful for the future. How not, when there is so much wonderful research out there like that of Prof O’Neill, his colleagues and collaborators, leading to positive change, to change for the better. This was one of many lectures and nearly 500 scientific posters presented in Dublin. Metabolomics is a powerful tool to uncover fundamental changes in biology which can lead to deep knowledge of cause and effect in disease. It is such a powerful tool that it is being applied very broadly in many research areas with exceptional growth in the number of peer reviewed articles that used metabolomics being very high year on year. Metabolomics is being applied to biomarker discovery in cancer and many other disease areas, to how we might grow better crop plants, in food safety and food quality, in clinical practice, to identify drug-induced markers of toxicity, in understanding nutrition, environmental contamination and so much more. It is already touching our lives and will continue to do so.

Useful videos

Compound Discoverer 2.0 customer video

Webinar: The Promise of Mass Spectrometry-Based Metabolomics for Clinical Research