Immunometabolism in glia
Immunometabolism is the study of how cellular inflammatory responses are influenced by metabolism (i.e., energy use), and vice versa. Inflammatory stimuli can change the metabolic spectrum in immune cells and, in turn, metabolic changes can direct the inflammatory response of these cells.
Our Work
A key focus of Dr Ellacott's group is understanding the interplay between metabolism and inflammation in the brain. We are particularly interested in how metabolism in the brain can determine or influence the inflammatory responses of glial cells. Glial cells are a group of brain cells that are important for supporting the function of nerve cells, and maintaining the integrity of the brain environment. This involves monitoring the brain environment for changes and responding appropriately. How well cells are able to use energy (as well as what source this energy comes from) is a major determinant of this function.
Why is this important? A wide variety of health conditions, including obesity and diabetes, ageing and age-related disorders, are associated with brain inflammation and altered brain (cognitive) function. This has been associated with memory issues, decline of general brain health, and has been shown to change dietary preferences. Interestingly, dietary intake has also been linked to brain inflammation. The inflammatory response in the brain is principally governed by two types of glial cells: microglia, the immune cells of the brain, and astrocytes, which are very important for regulating nerve activity, blood supply, and even feeding neurons. Crucially, changes to microglia and astrocytes are noted in a variety of disorders associated with brain inflammation.
We are interested in exploring the therapeutic value of modulating the metabolism of these cells, and investigating how this affects brain inflammation, in the hopes that this may contribute to treatments that will help treat brain inflammation and prevent the behavioural and cognitive changes associated with these conditions.
To do this, we use a variety of in vivo and in vitro assays including feeding studies, metabolic flux analysis, immunocytochemistry and immunohistochemistry, immunoblotting, cytokine analysis, and metabolite production assays.
Graphical abstract from Robb et al., 2019. A simplified schematic diagram of the proposed immunometabolic changes in astrocytes which may contribute to the CNS regulation of energy homeostasis – A variety of inputs, including nutritional stimuli (glucose, fatty acids, and branch chain amino acids [BCAA]), hormones (leptin and insulin) and cytokines can directly regulate cellular signalling and metabolic pathways in astrocytes. The signalling pathways implicated include signal transducer and activator of transcription 3 (STAT3), AKT, c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB), which in turn can impact astrocyte metabolism by modulating transcription or translation of key regulatory components of glycolysis and mitochondrial metabolism. Depending on the signalling pathway(s) activated and the energetic status of the cell, which is directly impacted by the CNS microenvironment, this leads to changes in levels of metabolic intermediates and products: lactate, ketones, reactive oxygen species (ROS), glutamine, and ATP. When released from the cell, these factors are capable of modulating synaptic transmission and function of neurons in energy homeostasis circuits in the CNS. Activation of astrocyte signalling can also lead to the production of cytokines, which may act in an autocrine or paracrine fashion to modulate neuronal and glial activity, potentially perpetuating a CNS proinflammatory microenvironment, such as in obesity or diabetes. In addition to modulating release of biochemical signalling modules, activation of astrocyte signalling can lead to changes in expression of structural proteins in astrocytes, such as glial-fibrillary acidic protein (GFAP), which enable morphological changes in astrocytes which impact neuronal transmission via ensheathment of synapses.
Publications
Robb JL, Hammad NA, Weightman Potter PG, Chilton JK, Beall C, Ellacott KLJ. The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.
Robb JL, Morrissey NA, Weightman Potter PG, Smithers HE, Beall C, Ellacott KLJ. Immunometabolic Changes in Glia - A Potential Role in the Pathophysiology of Obesity and Diabetes. Neuroscience. 2019 Nov 22. pii: S0306-4522(19)30708-0. doi: 10.1016/j.neuroscience.2019.10.021.