In a recent study funded by the British Heart Foundation, Guillaume Bidault and members of the TVP group, working with colleagues from the MRC LMB, provide some important new insights into how making fat in immune cells might help to fight disease.
Immune cell activation defends the body against foreign agents such as bacteria, viruses, or parasites. However, excessive immune cell activation is detrimental and can contribute to cardiometabolic complications associated with obesity and diabetes and to cancer progression. Understanding how immune cells fine-tune their activation is essential if we are to develop safe therapies for many human diseases.
Activated immune cells use sophisticated inflammatory weapons to fight infectious threats and require metabolic adaptations to meet the increased energy demands of their activated state. In many diseases, immune cell activation goes wrong (over or under activation). Immunologists became excited when it was shown that common metabolic pathways could govern immune cell activation. Modulating immune cells’ metabolism might allow fine-tuning of the immune system to treat disease more efficiently or to avoid damage caused by excessive immune activation. Our fundamental question was about how non-specialised metabolic pathways control inflammatory activation.
The authors studied the metabolism of ‘alternatively activated macrophages’ in mice. These immune cells are essential for eliminating parasites and regulating insulin sensitivity and cardiometabolic complications. They can also promote an immune-tolerant microenvironment that facilitates tumor growth and metastasis. They discovered that the proper activation of the macrophages requires activation of a metabolic process named de novo lipogenesis, a mechanism that transforms glucose into fat. Remarkably, blocking fat production shut down the capacity of these macrophages to become active.
Mice with a reduced capacity to make fat in their macrophages failed to defend themselves against parasitic infection and developed a more severe form of disease. But how does making fat contribute to activating these macrophages? A crucial insight is that when macrophages make fat, they cannot rid themselves of the products of oxidative stress because they use high amounts of a molecule named NADPH, which is also necessary to buffer oxidative stress. As a result, they accumulate reactive oxygen species that are essential to control macrophage activation.
This study shows that lipid anabolic pathways regulate a macrophage-specialised inflammatory function through their effects on redox status. The next question is whether this mechanism is also relevant in other diseases and whether making fat can regulate specialised functions in other cells that make their own fat (almost every cell in an organism!)