Macrophages are sentinel cells of the immune system that contribute to tissue homeostasis, however, upon sensing the presence of microbial or danger molecules, they initiate cascades of gene transcription to initiate inflammation. Our recent work focused on how changes in macrophage metabolism promote transcriptional programmes. We discovered that within a time frame relevant for signalling-induced transcriptional responses, TLR4 signalling in macrophages led to increased glucose uptake, amplified glycolysis and increased TCA cycle volume, which, in turn, resulted in high amounts of citrate. By activating ATP-citrate lyase (ACLY) via phosphorylation, TLR4 signalling, further enhanced acetyl-Coenzyme A (CoA) levels, which resulted in a rapid de novo acetylation of lysine residues on histones H3 and H4. ACLY-mediated histone acetylation facilitated the induction of a defined set of genes that are implicated in inflammation and cellular defence mechanisms. We, therefore, suggest that signalling-induced metabolic reprogramming licenses macrophages to respond to many cues from the environment with tissue- and context-adapted transcriptional programmes. Accordingly, we reason that redirecting metabolic fluxes in macrophages holds great potential to facilitate beneficial effector functions or, conversely, restrict inflammation that might cause pathologies linked to metaflammation. Indeed, maladapted or prolonged metabolic reprogramming of macrophages has been linked to the progression of many pathological processes, providing a rationale for targeting mito-nuclear signalling axis in macrophages in the context of inflammatory diseases linked to metaflammation.
In this project, two labs with complementary expertise in innate immunity, metaflammation and immunometabolism and a proven track record of collaboration, will work together with the goal to understand how ACLY affects macrophage phenotypes in metaflammation and promotes disease progression in the context of obesity and hyperglycaemia. In Aim 1, the role of ACLY in macrophage epigenetic and metabolic reprogramming in the context of obesity will be defined. Aim 2 will identify whether known triggers of metaflammation and other inflammatory substances can license inflammatory signalling via the ACLY-inflammation axis. Aim 3 will investigate the role of increased glucose levels for chronic macrophage metabolic reprogramming, and in Aim 4 mitochondrial metabolism as acetyl-CoA fuel will be evaluated in the context of diet or obesity-associated metaflammation. Together, this work will characterise the function of a novel mito-nuclear signalling pathway in metaflammation and could lead to novel biomarkers strategies for therapeutic intervention in diseases linked to metaflammation.