Every cell in our body requires energy to perform their specific functions. Generally, this is a well-controlled and ordered process. However, in some settings, the ways in which cells obtain this energy is altered and has important functional consequences.
We are now learning that the metabolism of immune cells is intricately linked to their function, where distinct metabolic configurations are ascribed to different phenotypes.
Our research aims to understand the link between what immune cells ‘eat’ in our tissues and how this is connected to their normal biology and inflammatory diseases such as high blood pressure and diabetes.
Research areas
Effect of dietary salt on macrophage metabolism and function
Macrophages are innate immune cells that acquire specialised pro- or anti-inflammatory functions upon responding to stimulatory cues (e.g. toll-like receptor agonists and cytokines) in their local tissue environment.
It has recently emerged that small molecules, such as metabolites and electrolytes, have significant effects on macrophage phenotypes via ‘reprogramming’ their cellular metabolism; involving the activation of signalling pathways, expression of metabolic enzymes and proteins, increased uptake and storage of nutrients, and physical remodelling of mitochondria.
We previously reported that high dietary salt increased sodium (Na+) in tissues that subsequently modulated macrophage phenotypes: increasing pro-inflammatory responses and glycolytic metabolism, while inhibiting protective anti-inflammatory functions and mitochondrial respiration (Binger et al., J Clin Invest 2015; Jantsch et al., Cell Metab 2015). The aim of this project is to understand how sodium reprograms macrophage metabolism.
Development of 3D cultures to better model macrophage biology and function
Macrophages are unique in that they are the only immune cells derived from two developmental origins: from progenitors, which seed all tissues during embryonic development, and on command from haematopoietic stem cells, which give rise to circulating precursors that infiltrate tissues throughout adulthood (Wright & Binger. Pflugers Arch 2017).
Macrophages have general roles in clearing invading pathogens and apoptotic cells and promote tissue repair by producing extracellular matrix proteins such as fibronectin and collagen. Macrophages derived from embryonic precursors are known as tissue-resident macrophages (TRM), given that they are seeded during the development of their respective tissues and reside with limited renewal from haematopoietic precursors. As the tissue environment is a major controller of TRM function, understanding their function with classical 2D in vitro culture systems is impossible. The aim of this project is to develop 3D systems that better recapitulate the tissue microenvironment and support TRM function.
Identification of macrophage surface protein-ECM protein interactions
Macrophages are innate immune cells that are present in all our tissues – either residing there from embryonic development or infiltrating on command, for example during infections.
There is emerging evidence that the interaction of macrophages with their tissue-specific extracellular environment is an important modulator of their biology. Macrophages interact with the extracellular matrix (ECM) of their respective tissue via proteins such as integrins; heterodimeric receptors that are essential for the adhesion of cells to the ECM. The organisation and subsequent signalling of many integrin subunits are regulated by tetraspanins, a family of four-transmembrane proteins that interact with a variety of partner proteins (including integrins), and each other, to organize tetraspanin-enriched microdomains at the cell membrane.
Our preliminary data shows that macrophages deficient for the tetraspanin CD82 exhibit altered function coupled with reduced expression of integrins and altered metabolism. Correspondingly, a recent study showed the differentiation of human induced pluripotent stem cells (iPSCs) into microglia-like macrophages was concurrent with an upregulation of CD82 and other tetraspanins CD9 and CD53, suggesting an essential, but largely understudied, role for tetraspanins in macrophage biology. This project aims to identify sensors of the macrophage extracellular environment. This will be achieved by employing an untargeted proximity labelling proteomics experiment, where the promiscuous biotin ligase TurboID is cloned to either the N- or C-terminal end of the protein of interest.
