Why does obesity so often go hand in hand with seemingly unrelated chronic diseases such as cancer, Alzheimer’s and asthma? As it turns out, obesity puts the body in a constant state of low-grade inflammation, which is linked to these conditions.
This link between metabolism and the immune system is true at the cellular level too. Identifying which cells contribute to a particular metabolic function or disease state could therefore yield valuable insight into the subtleties of the immune system.
Now, a team led by John Connolly, a Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), has developed a new method that reliably captures immune cell metabolic pathways for analysis at single-cell resolution. Connolly’s team collaborated with US medical technology company Becton Dickinson on this project.
Aptly named Met-Flow, the flow cytometry-based method can determine the metabolic state of immune cell subpopulations with divergent metabolic profiles by using antibodies that target key proteins and rate-limiting enzymes across multiple metabolic pathways.
“Previous flow cytometry-based methods with dyes only allow for the determination of the state of one metabolic pathway at a time. These methods are also associated with spectral bleed-through when combined with fluorescent antibodies to determine cell type,” Connolly said. “Met-Flow provides important insights into the understanding of the metabolic state across any cell type.”
In Met-Flow, immune cells are first stained with fluorescently labeled antibodies to determine their subtype and then intracellularly stained once again to determine their metabolic state. Using this strategy, researchers can draw associations between the metabolic profile of a cell with its features, activation status and immunological function, which has implications for treatment design in the context of different metabolic states and immunological microenvironments in disease.
Met-Flow has already been put through its paces. Using this method, the researchers discovered that immune activation causes a widespread change in sugar, protein, electrolyte and fatty acid processing, generating metabolic signatures sufficient to identify specific white blood cell subtypes. In turn, manipulating sugar metabolism also transforms T cell activation pathways; in particular, the team found that glucose restriction and metabolic remodeling caused the expansion of one specific inflammatory memory T cell subpopulation, the central memory T cells.
The researchers say they would like to expand the use of Met-Flow to investigate metabolic remodeling in more cell types and disease conditions, such as in cancer, inflammatory disorders and autoimmune disease.
“The metabolic state of an immune cell ultimately determines its function, and so by understanding their metabolic status we can better formulate novel treatments for disease,” Connolly said.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).