Navigating metabolism, the sum total of all the chemical interconversions going on in a cell, is like navigating the London underground. It’s incredibly confusing to the outsider and necessitates precise control mechanisms of its interconnecting pathways. Key chemicals form nodes or junctions and can go down multiple overlapping lines, building and degrading all the components that a cell needs. A given cell has the capacity to use all these pathways but, just as the number of people using the underground varies, so too does the flux of activity down metabolic pathways.
Such a system must be flexible in order to cope with fluctuating demands of different types of cells. White blood cells, the armoury of our immune system, must rapidly alter their metabolism when faced with the strain of infection.
If metabolism is the London underground, then having an infection is the summer rush hour. Metabolic capacity is stretched to breaking point. To alleviate this pressure, immune cells rewire their metabolic pathways by switching to ‘Warburg’ metabolism whereby energy is generated by a non-oxygen consuming pathway making lactate, the molecule suspected to be responsible for muscle cramp.
In addition to this general energy switch, subtle metabolic differences exist between different subtypes of white blood cells that specialise them to their specific functions. Inflammation-causing white blood cells, for instance, have the metabolic machinery to produce reactive nitric oxide which acts as a toxic bullet against pathogens, whereas tissue repairing white blood cells do not.
Partitioning of cellular jobs is important because the immune system has dual functionality. Not only must it destroy foreign cells, but also, simultaneously, limit lateral damage by protecting the body’s own healthy cells. By characterising the metabolic profiles of immune cells in health and disease, scientists hope to be able to reprogramme faulty metabolic circuits. This could form a novel treatment for autoimmune diseases such as multiple sclerosis and some cancers which occur when the immune system destroys its own cells.
“The hope is that simple manipulation of key pathway components will enable some simple reprogramming that will have minimal side effects,” says Professor Luke O’Neil, Professor of Immunology at Trinity College Dublin. He highlights recent findings showing the efficacy of a treatment for preventing organ rejection using metabolic pathway inhibitors, including an existing type II diabetes drug.
Furthermore, there is scope to improve existing socalled ‘immunotherapy’ to turn the patient’s own immune system on the patient’s own disease. In one such therapy, adoptive cell transfer, white blood cells engineered for a therapeutic function are introduced into the body. Professor O’Neil explains that “immunotherapies will undoubtedly benefit from any [metabolic reprogramming] strategy that maintains their functional state in the body, or that alternately rapidly turns them off if they cause side effects.”
The complexity and integrated nature of metabolic pathways makes progress in this area challenging and slow, yet a revival of the importance of metabolism in biochemistry is heralding progress in elucidating immune pathways and paving the way for therapeutic applications.
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